Chapter 4

Mechanisms of Irritant Contact

Dermatitis

Steen Lisby, Ole Baadsgaard

Contents
4.1

Introduction

. . . . . . . . . . . . . . . . . .

69

4.2
4.2.1
4.2.2
4.2.3

70
70
70

4.2.4

Clinical Spectrum of Irritant Skin Reactions

Subjective Irritant Reaction . . . . . . . . . .
Acute Irritant Contact Dermatitis . . . . . .
Chronic (Cumulative) Irritant Contact
Dermatitis . . . . . . . . . . . . . . . . . . .
Chemical Burn . . . . . . . . . . . . . . . . .

4.3
4.3.1
4.3.2

Skin the Outpost of the Immune System .

Immunocompetent Cells of the Skin . . . . .
Skin Infiltrating T Lymphocytes . . . . . . .

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71
72

4.4

Pathogenesis of Acute Irritant Contact

Dermatitis . . . . . . . . . . . . . . .
Skin Barrier Perturbation . . . . . . .
Cellular Immunological Changes
in Irritant Contact Dermatitis . . . .
Epidermal Cytokines Involved
in Irritant Contact Dermatitis . . . .

4.4.1
4.4.2
4.4.3

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71

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. . . .

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73

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74

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75

4.5

Irritant-induced Interleukin-1

. . . . . . . .

76

4.6

Irritant-induced TNF- . . . . . . . . . . . .

76

4.7

Mechanisms of Irritant-induced TNF-

in Keratinocytes . . . . . . . . . . . . . . . .
Regulation of the Inflammatory Milieu
Locally in Inflamed Skin . . . . . . . . . . . .

4.7.1
4.8

tration, and vesiculation. In its more chronic form,

dryness, fissuring, and hyperkeratosis are more pronounced. It is thus clear that the clinical reaction pattern of mild to moderate irritant contact dermatitis
is often indistinguishable from the allergic contact
dermatitis reaction. Thus, differentiation between
these two reaction types is often based solely on patient history and skin allergy tests. Despite the common hallmarks of irritant contact dermatitis, the
clinical manifestation of the skin lesions developing
following contact with different irritants varies. Factors that may influence the outcome of skin contact
with irritants can be divided as follows:

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Hypothesis of the Immunological Events

Leading to Irritant Contact Dermatitis . . . .

79

Suggested Reading . . . . . . . . . . . . . . .

80

References

80

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4.1 Introduction
Irritant contact dermatitis is an eczematous reaction
in the skin of external origin. In contrast to allergic
contact dermatitis, no eliciting allergens can be identified. The spectrum of irritant reactions includes
subjective irritant response, acute irritant contact
dermatitis, chronic irritant contact dermatitis, and
chemical burns (Table 1). Irritant contact dermatitis
is in its acute form characterized by erythema, infil-

Exogenous: such as structural and chemical

properties of the irritant, exposure to other
irritants, and environmental conditions, e.g.,
temperature and humidity.
Endogenous: such as body region that is
exposed (the scrotum is much more sensitive
than, e.g., the upper back), age [1], race [2],
and pre-existing skin disease.

Moreover, in addition to the capacity of different irritants to induce clinically different reactions, it has
been reported that marked interindividual variation
in the threshold for eliciting clinical irritant reaction
in skin is present [3].
In the past, the pathogenesis of irritant contact
dermatitis was thought to be nonimmunological.
However, today it is generally accepted that the immune system plays a key role in eliciting irritant reactions. This has been underscored by human and
animal studies demonstrating the importance of sig-

Table 1. Type of irritant reactions

Subjective irritant reaction (stinging)
Acute irritant contact dermatitis
Chronic irritant contact dermatitis
Chemical burn

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Steen Lisby, Ole Baadsgaard

nal molecules, e.g., cytokines, in eliciting the irritant

reaction.

Core Message

Irritant contact dermatitis is an eczematous reaction in the skin caused by exposure to external agents/chemicals. Clinically the reaction manifests similar to the
allergic contact dermatitis reaction.

4.2 Clinical Spectrum

of Irritant Skin Reactions
The spectrum of the clinical appearances of irritant
contact dermatitis is extremely broad. It is therefore
widely accepted that no single mechanism underlying the development of this disease entity exists. In
this chapter, we briefly outline the different clinical
reaction types. For more extensive description, the
reader is referred to Chap. 15.

Core Message
Irritant contact dermatitis can be divided
into different reaction types, including
stinging, acute irritant reaction, chronic
irritant reaction, and chemical burn.

Table 2. Chemicals involved in subjective skin reactions

(adapted from [4])
Immediate stinging potential
Chloroform
Methanol
Hydrochloric acid
Retinoic acid
Delayed stinging potential
Weak:
Aluminum chloride
Benzene
Phenol
Phosphoric acid
Resorcinol
Salicylic acid
Moderate:
Propylene glycol
Dimethylsulfoxide
Benzoyl peroxide
Severe:
Crude coal tar
Lactic acid
Hydrochloric acid
Sodium hydroxide
Amyldimethyl-p-aminobenzoic acid

4.2.2 Acute Irritant Contact Dermatitis

This type of reaction is often the result of a single exposure to an irritant. The clinical appearance is very
variable and often indistinguishable from the allergic
contact dermatitis reactions. The manifestation may
vary from a little dryness and redness to severe reactions with edema, inflammation, and vesiculation.
Often the clinical reactions are located to areas of exposure and the skin manifestations often disappear
within days to weeks.

4.2.1 Subjective Irritant Reaction

The hallmark of this type of irritation is the lack of
clinical manifestation. Subjective registration of a
burning or stinging feeling following contact with
certain chemicals is diagnostic (Table 2). Despite no
clinical manifestation, the reaction can be reproduced. Typically, symptoms occur rapidly following
exposure (i.e., within seconds to minutes). There
seem to be interindividual differences in eliciting this
type of reaction, and several studies have classed individuals as sensitive (stingers) and nonsensitive
(nonstingers) [4]. One example of immediate stinging is the appliance of a mixture of chloroform and
methanol to the skin. In stingers, even when applied
to intact skin, a sharp pain develops within seconds
to minutes following exposure to the chloroform/
methanol mixture [5].

4.2.3 Chronic (Cumulative) Irritant Contact

Dermatitis
This type of reaction develops as a result of cumulative exposures of the skin to irritants. Clinically, this
type of reaction is characterized by dryness, redness,
infiltration, scaling, fissuring, and vesiculation to only a minor degree. Often this type of irritant contact
dermatitis is located on the hands. A hallmark of this
type of reaction is its chronicity. Despite removal of
irritant exposure, the clinical reaction may continue
for several years. Several external factors are known
to contribute to elicitation of chronic irritant eczema.
These agents include water, detergents, organic solvents, oils, alkalis, acids, oxidizing agents, heat, cold,
friction, and multiple microtrauma.

Mechanisms of Irritant Contact Dermatitis

4.2.4 Chemical Burn

Reactions are induced by highly alkaline or acid compounds. These agents can result in severe damage of
the skin. The reaction often develops within minutes,
and frequently manifests with the appearance of a
painful erythema, followed by vesiculation, and the
formation of necrotic scars. This type of reaction is
often sharply demarcated and may lead to deep tissue
destruction even after only a short exposure.

4.3 Skin the Outpost

of the Immune System
To understand the pathogenic mechanisms involved
in irritant contact dermatitis, it is important to address the involvement of the different cell types constitutively present within the skin, and the cell types
that can be recruited to the site of the irritant reaction as well as the proinflammatory and inflammatory mediators induced by the different cell populations following irritant exposure.

4.3.1 Immunocompetent Cells of the Skin

The outermost part of the skin is the epidermis. Epidermis is mainly composed of keratinocytes, Langerhans cells, and melanocytes. Both keratinocytes and
Langerhans cells are involved in immunological processes. In contrast, the immunological importance of
the epidermal melanocyte, if any, is not known.
The involvement of the keratinocyte in the skin
immune system was first indicated in 1981/1982 by
Luger et al. and Sauder et al. who described a keratinocyte-derived cytokine, epidermal-derived thymocyte activating factor (ETAF) [6, 7]. The majority of
ETAF activity was later confined to interleukin-1 (IL1). It has now been demonstrated that the keratinocyte is capable of producing a variety of immunological active cytokines/factors (Table 3), including IL-1,
IL-6, IL-8, IL-10, IL-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis
factor-alpha (TNF-), and transforming growth factor-beta (TGF-). The involvement of some of these
factors in irritant contact dermatitis is reviewed later
in this chapter. Beside cytokine expression, keratinocytes can be induced to express or increase expression of major histocompatibility complex (MHC)
molecules [8, 9] and cell adhesion molecules such as
intercellular adhesion molecule-1 (ICAM-1) [10, 11].
Expression of these molecules, in combination with
the release of chemotactic cytokines, and factors involved in the upregulation of E-selectin and vascular

Chapter 4
Table 3. Keratinocyte-derived cytokines
Interleukin-1
Interleukin-1
Interleukin-3
Interleukin-6
Interleukin-7
Interleukin-8
Interleukin-10
Interleukin-12
Interleukin-15
Interleukin-18
Tumor necrosis factor-
Transforming growth factor-
Transforming growth factor-
Granulocyte colony-stimulating factor
Granulocyte-macrophage colony-stimulating factor
Platelet-derived growth factor
Epidermal cell-derived lymphocyte differentiation
inhibiting factor
Keratinocyte lymphocyte inhibitory factor

cell adhesion molecule-1 (VCAM-1) on dermal endothelial cells [12], makes the keratinocyte an important player in the induction and maintenance of inflammatory cells within the skin.
The epidermal Langerhans cell is the only cell
type in normal epidermis that exhibits all accessory
cell functions and thus acts as a complete antigenpresenting cell. The epidermal Langerhans cell was
originally described in 1868 by Paul Langerhans [13]
and comprises 25% of the total epidermal cell population. It is constitutively present in the skin and is localized to the suprabasal part of the epidermis. The
Langerhans cell is a dendritic, bone marrow-derived
cell characterized by surface expression of type-1a
cluster of differentiation (CD1a) antigen, as well as
MHC class I, and MHC class II (HLA-DR, -DP, -DQ)
molecules. Ultrastructurally, the Langerhans cell
contains characteristic intracytoplasmic Birbecks
granules. Beside its capacity to present antigens to Tcells, the Langerhans cell is capable of secreting cytokines such as IL-1, IL-6, IL-10, IL-12, and TNF- [14].
The Langerhans cell has been implicated in the immune surveillance of the skin; it is also required for
induction of primary immune responses in skin, and
as such is suggested to be a key player in allergic contact dermatitis. In addition, recent research has associated this cell type with events occurring during the
development of irritant contact dermatitis.
Several dermal antigen-presenting cell subsets
have been described including macrophages and
dendritic cells. Macrophages are bone marrow-de-

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Steen Lisby, Ole Baadsgaard

rived cells with a broad range of functions, including

antimicrobial activity, anti-tumor activity, regulation
of B and T lymphocytes, release of cytokines and
processing antigens thereby functioning as antigen-presenting cells. These cells are characterized by
surface expression of Fc-receptors, including CD16
and CDw32, and MHC class II molecules. Furthermore, these cells express LFA-1 (CD11a) and when activated also CD11b.
In ultraviolet-irradiated skin, dermal and epidermal monocyte/macrophage-like cells expressing a
HLA-DR+, CD11b+, CD36+ phenotype have been observed [15]. These cells are involved in downregulation of the immune response, revealed by their capacity to preferentially activate CD4+ suppressor-inducer T lymphocytes [16, 17]. In addition, these
CD11b+, MHC class II+ cells were found to secrete
large amounts of IL-10, in contrast to the residual epidermal Langerhans cells, which secrete mainly IL-12
[18]. Thus, different bone marrow-derived cells of the
macrophage or dendritic cell lineage are differently
involved in the ongoing immune regulation within
the skin during an inflammatory reaction.
In skin diseases, such as mycosis fungoides and
contact dermatitis, cells with a similar HLA-DR+,
CD36+ phenotype have been detected within the epidermis [19, 20]. Their functional role is underscored
by observations that depletion of the epidermal
Langerhans cells only partially inhibits an autologous
epidermal lymphocyte reaction. Furthermore, when
isolated from involved epidermis, HLA-DR+, CD36+
cells exhibit the capacity directly to stimulate autologous T lymphocytes in vitro [21]. In addition, HLADR+, CD36+ cells have been observed in the irritant
reaction [22]. However, their functional role in the development of an irritant reaction is still unknown.

Core Message
Immunocompetence of normal epidermis
is restricted to the epidermal Langerhans
cell. In irritant contact dermatitis, other
dendritic cells are present, and the keratinocytes develop immunoregulatory functions, including but not limited to MHC
class II and ICAM-1 expression.

4.3.2 Skin Infiltrating T Lymphocytes

It has been known for several years that many skin
diseases are characterized by skin infiltration by T

lymphocytes. These T lymphocytes often express a

CD3+, CD4+ phenotype, although CD8+ T lymphocytes are also present. While trafficking the skin,
these T lymphocytes are capable of releasing a variety of cytokines, including IL-2, IL-4, IL-10, interferon (IFN-) and TNF-. Based on their cytokine secretion, T lymphocytes can be divided into T helper-1like (Th1-like), Th2-like or Th0-like cells (Table 4).
This division was originally suggested in 1986 by
Mosmann et al. based on investigation of murine T
lymphocyte clones [23]. He distinguished two different subsets of T lymphocyte clones. The first was
named Th1 and comprised clones preferentially producing IL-2 and IFN-, while the other group of
clones was termed Th2 and produced large amounts
of IL-4 and IL-5. Following this observation, several
studies have included more cytokines in this subdivision and furthermore suggested a similar division of
human T lymphocytes. Many of the T lymphocytederived cytokines are involved in regulation of inflammatory processes. IL-2 is known as a T lymphocyte growth factor, another cytokine like IFN- is involved in the induction or upregulation of cell adhesion molecules [10], and IL-10 downregulates Th1type cytokine secretion [24] and thus acts as an inhibitory molecule.
In humans, a disease such as atopic eczema is characterized by skin infiltration by T lymphocytes expressing a Th2 like profile in its acute phase whether
the skin-infiltrating T lymphocytes in allergic contact
dermatitis, psoriasis, and late-phase chronic atopic
dermatitis express a Th1 like profile. In irritant contact dermatitis, studies investigating cytokine profiles
in the acute reactions have mainly detected increased
levels of IL-2 and IFN-, thereby indicating a Th1-cytokine profile, as discussed in this chapter.
Recent, it has been demonstrated that T lymphocytes entering the skin often are characterized by increased expression of a surface molecule cutaneous
lymphocyte-associated antigen (CLA) [25]. This
molecule participates directly in transendothelial
migration of T lymphocytes. The ligand for CLA is ETable 4. T helper (Th) lymphocyte cytokine profiles: cytokines
predominant in the different groups
Th1

Th2

Th0

IFN-
IL-2
TNF-
TNF-

IL-4
IL-5
IL-6
IL-9
IL-10
IL-13

INF-
IL-2
IL-4
TGF-

Mechanisms of Irritant Contact Dermatitis

selectin, which is found to be upregulated in various

skin diseases, including contact dermatitis. Other receptor-ligand pairs, such as lymphocyte function-associated antigen (LFA)-1/ICAM-1 and very late antigen-4 (VLA-4)/VCAM-1, are also involved in this process [26]. The importance of CLA has been demonstrated by blocking CLA in vitro, which resulted in
inhibition of transendothelial T lymphocyte migration [26]. Furthermore, studies on T lymphocytes
from individuals with contact allergic dermatitis
have revealed that preferentially CLA+ cells are activated and recruited to the skin [27]. Thus, the importance of CLA as a selective skin homing receptor for
T lymphocytes has been established and this molecule seems to play an important role in the recruitment of T lymphocytes to the local inflammatory reaction site in the skin. Despite these observations, the
role of CLA expression in irritant contact dermatitis
is still not clarified.

Core Message
Inflammatory skin diseases, including irritant contact dermatitis, are characterized
by influx of activated T lymphocytes. In
general the skin-infiltrating T lymphocytes
express CLA; however, their role in irritant
contact dermatitis is unknown. In irritant
contact dermatitis, studies investigating cytokine profiles are preferentially performed
in the acute reactions and these investigations have detected increased levels of IL-2
and IFN- and thereby indicate a Th1-cytokine profile.

4.4 Pathogenesis of Acute Irritant

Contact Dermatitis
Research within the field of irritant contact dermatitis has primary been focused on the development of
the acute irritant reaction and only to a lesser degree
the chronic irritant reaction. For many years researchers have tried to differentiate between the allergic and irritant skin reactions by the means of histopathology or immunohistopathology [28, 29] as
described in Chapter 8. However, only minor differences have been revealed. Until recently, skin irritation was thought to be a nonimmunological reaction
in the skin; however, recent work has indeed implicated the immune system in the development and
maintenance of irritant-induced skin reactions. In

Chapter 4

contrast to allergic skin reactions, no immunological

memory seems to be involved in eliciting irritant
contact dermatitis and the development of irritant
skin reactions does not require prior sensitization.
Although chemical differences exist between different irritants, exposure of the skin to irritants often
lead to skin barrier perturbation, skin infiltration by
immunocompetent cells, and induction of inflammatory signal molecules.

4.4.1 Skin Barrier Perturbation

One major finding following exposure to skin irritants is perturbation of the skin barrier. The skin
barrier is composed of the outermost layer of the epidermis the stratum corneum. The stratum corneum consists of protein-rich cells, the corneocytes,
which are embedded within a continuous lipid-rich
matrix. Within the stratum corneum, the barrier
function is mainly confined to the inner one-third
included within the compact part of the stratum corneum [30]. The dynamic process of damaging and
re-normalization of the skin barrier can be quantified using a noninvasive technique based on the
measurement of transepidermal water loss (TEWL).
This method has today been accepted as a reliable
marker of skin barrier disruption. Much research has
been conducted using the anionic surfactant sodium
lauryl sulfate (SLS).Application of SLS to human skin
results in perturbation of the skin barrier and an increased TEWL measurement as compared to control
values [31]. This effect is not only a transient phenomenon. Increased TEWL values have indeed been
observed more than 6 days following exposure to SLS
[32]. In addition, another study demonstrated that
complete recovery of the skin barrier was first obtained more than 3 weeks after irritant challenge [33].
This was demonstrated by re-testing the irritanttreated skin area with the same irritant. Thus, longlasting perturbation of the skin barrier is observed
following SLS challenge of the skin in vivo.
The mechanisms behind the irritant-induced barrier perturbation are not fully understood; however,
increased hydration [34] and disorganization of the
lipid bilayers of the epidermis [35] have been reported. Although one could argue that disruption of the
skin barrier is merely a mechanical change of the
skin, several studies have demonstrated the importance of an intact stratum corneum. Disruption of
the barrier could actually result in the induction of a
danger signal. In support of this, it has been demonstrated that acetone treatment or impeachment of
the skin barrier by tape stripping results in increased
mitotic activity in the basal keratinocytes [36]. Fur-

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Steen Lisby, Ole Baadsgaard

thermore, studies have indicated that, following disruption of the skin barrier, increased levels of immunological active signal molecules, in particular IL-1,
IL-1, TNF- and GM-CSF, are present within the
skin [37]. Thus, taken together, perturbation of the
skin barrier itself could actually initiate an immunological stress signal leading to the subsequent development of an inflammatory reaction locally in the
skin.
Finally, an impaired skin barrier also facilitates
skin penetration by the irritant itself, or by other external agents including allergens and bacteria. Thus,
perturbation of the skin barrier is thereby implicated
in many skin diseases and thought to be a major
player in the induction of irritant contact dermatitis.

Core Message
One hallmark of irritant exposure is perturbation of the skin barrier. This facilitates penetration by external agents and by
itself induces inflammatory signals locally
in challenged skin.

4.4.2 Cellular Immunological Changes

in Irritant Contact Dermatitis
As described above, the skin, which is the outermost
outpost of the immune system, is an organ essential
for the initiation and maintenance of contact dermatitis.Although much research has been focused on allergic contact dermatitis, numerous studies have
characterized the cellular infiltrate in irritant contact
dermatitis, especially the experimentally induced
acute irritant reaction. The histological manifestation of the irritant reaction is often impossible to distinguish from the manifestation observed in the contact allergic reaction [28, 29]. In addition, diversity of
the histopathological changes is seen following skin
exposure to different irritants [38]. However, the cellular infiltrate is characterized mainly by mononuclear cells in particular T lymphocytes belonging to
the CD4+ subset [39, 40]. These T lymphocytes detected in irritant contact dermatitis seem to belong
to a Th1-like subpopulation, as the major T lymphocyte cytokines detected are IFN- and IL-2 [41]. This
observation parallels findings in allergic contact dermatitis. Furthermore, a study has shown that in both
allergic and irritant skin reactions, an increase in
number of CLA+ T lymphocytes is observed in the
skin [42]. This study was, however, performed on

atopic individuals. Another study also found an increase in CD3+ cells in skin biopsy samples from irritant reactions, however in this study they actually observed a decreased percentage of CLA+ cells as compared to samples from atopic dermatitis skin [43].
Furthermore, the same study found marked expression of integrin 47 by T lymphocytes present in
the skin [43]. 47 is a gut homing marker and skin
expression of this molecule suggests that a nonspecific influx of T lymphocytes has occurred and that
CLA is not a prerequisite for cutaneous T lymphocyte infiltration [43, 44]. Thus, the precise role of CLA
in irritant contact dermatitis is still not clearly
understood.
In addition to CLA-positive T cells, new information has implicated cells expressing IL-2 receptor
(CD25) in the regulation of inflammation in tissues,
including the skin. The CD25-positive T cells seem to
be downregulators of inflammation and thus involved in the regulation and termination of inflammatory processes. In allergic contact dermatitis, a decreased number of CD25-positive cells has been observed in involved skin (nickel allergic patch tests)
compared to normal skin. However, it is imperative
to state that a role for CD25-positive T cells in the development and maintenance of the irritant reaction
is currently unknown.
Many studies have implicated the keratinocyte as
an important player in the induction of immunological changes observed in irritant contact dermatitis
(Fig. 1). The effect of irritants on the epidermal keratinocytes varies depending on the exposure. Strong
acids or alkalis often result in necrosis of keratinocytes. In contrast, following damage to the skin barrier
by tape-stripping or irritant challenge using SLS, an
increased mitotic activity in keratinocytes has been
observed [36, 45]. At the histopathological level, irritants exhibit different effects on keratinocyte morphology. Willis et al. [38] evaluated clinical and histological changes in skin following 48 h of exposure to
different irritants [38]. Nonanoic acid induced eosinophilic degeneration of keratinocytes with nuclear
degeneration and only minimal spongiosis. Croton
oil produced considerable spongiosis, and the presence of intracytoplasmic vesicles in the upper dermis
was observed. SLS induced minor morphological
changes in the keratinocytes and induced parakeratosis, suggesting increased epidermal turnover. Finally, ditranol induced a marked swelling of the keratinocytes in the upper epidermis. Thus, specific changes of keratinocytes can be observed following exposure to structurally different irritants. In addition to
inducing morphological changes in the skin, irritants
are also capable of upregulating cell surface molecules on epidermal cells. One important observation

Mechanisms of Irritant Contact Dermatitis

75

Chapter 4

Fig. 1.
Keratinocyte responses to
skin irritants

is the capacity to upregulate MHC class II expression

on keratinocytes [46]. This upregulation is also observed in the contact allergic reaction. Furthermore,
induction of adhesion molecules such as ICAM-1 on
keratinocytes has been demonstrated [47] and this
molecule, possibly in combination with irritant-induced upregulation of E-selectin on endothelial cells
[48], is known to be involved in T lymphocyte accumulation within the skin. Finally, irritant challenge
results in the release of several keratinocyte-derived
cytokines, as discussed later.
The involvement of the epidermal Langerhans cell
in irritant contact dermatitis is still unclear. Some
studies have indicated that the number of epidermal
Langerhans cells remain unaltered in the skin. In
contrast, other studies have demonstrated a decrease
in epidermal Langerhans cell numbers following irritant challenge [22, 4951]. The effect of irritants on
Langerhans cell number was long lasting, and full recovery was first obtained 4 weeks following irritant
challenge [22]. In support of the latter observation,
increased numbers of Langerhans cells have been
identified in the afferent lymphatic system following
irritant challenge of human skin [52, 53]. However,
one must consider that chemically different irritants
might have different capacities to modulate Langerhans cell numbers. Accordingly, different effects on
Langerhans cell numbers have been observed when
comparing SLS and nonanoic acid (NAA) [54].

Core Message
The histological manifestation of the irritant reaction is often impossible to distinguish from the contact allergic reaction.
Furthermore, diverse histopathological

changes are seen following skin exposure

to different irritants. In general, during the
acute phase of the irritant reaction, a decrease in epidermal Langerhans cells number is observed, and upregulation of MHC
class II and ICAM-1 on keratinocytes is
demonstrated.

4.4.3 Epidermal Cytokines Involved

in Irritant Contact Dermatitis
As discussed before, both keratinocytes and Langerhans cells exhibit the capacity to secrete a variety of
immunologically active cytokines. In irritant contact
dermatitis many cytokines have been found to be upregulated as compared to normal, uninvolved skin
(Table 5).Although demonstration of increased levels

Table 5. Cytokines upregulated in irritant contact dermatitis

In vivo
Interleukin-1
Interleukin-1
Interleukin-2
Interleukin-6
Interleukin-8
Interleukin-10
Tumor necrosis factor-
Granulocyte-macrophage colony
stimulating factor
Interferon-

In vitro

[41, 55]
[56, 57]
[41]
[57, 58]
[59]
[56]
[60, 61]
[60]
[41, 60]

[62]

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Steen Lisby, Ole Baadsgaard

of cytokines in the irritant reaction is well established both in vivo and in vitro, different results are
published in the literature as to which cytokines actually are increased. Many studies have investigated
one or two irritants, and generalized from these data.
However, today it is known that the application of
different irritants to the skin results in the induction
of different cytokine profiles. One example is a study
by Grngsj et al. demonstrating that in contrast to
SLS, NAA is capable of upregulating IL-6 mRNA in
human skin [63]. Similar, several irritants including
SLS, but not benzalkonium chloride, have been demonstrated to upregulate TNF- [58]. The complexity
of irritant-induced cytokine profiles in skin is further underscored by the findings that SLS, phenol,
and croton oil all upregulate IL-8 whereas only croton oil upregulates GM-CSF [64]. Thus, differences
exist in the capability of irritants to induce cytokines. Of the many irritant-inducible cytokines (see
Table 5), the pro-inflammatory cytokines IL-1, IL1, and TNF- are of particular interest.

4.5 Irritant-induced Interleukin-1

Interleukin-1, which was first isolated from monocytes, is now known to be synthesized in several cell
types, including keratinocytes. IL-1 exists in two
functionally active forms: IL-1 and IL-1.
In normal skin, IL-1 is constitutively produced
by the keratinocytes, and damaging the cell membrane can result in the release of pre-formed IL-1 to
the intercellular space. IL-1 is the major form of
IL-1 produced by keratinocytes and is secreted as an
active molecule. In contrast, IL-1 is secreted as a
31-kDa biologically inactive precursor, which has to
be cleaved into an active 17.5-kDa molecule by a protease, not present in resting human keratinocytes.
However, in activated keratinocytes, mRNA of IL-1converting-enzyme was readily detected following
incubation with the hapten urushiol or the irritants
phorbol myristate acetate (PMA) or SLS [65]. Thus,
even though the keratinocyte is not capable of synthesizing immunological active IL-1 in intact skin,
this capacity can be induced by external inflammatory signals. The mechanism for this induction remains unclear. IL-1 is a multifunctional cytokine
[66], implicated in T lymphocyte activation and IL-2
production. In addition, IL-1 is involved in upregulation of IL-2 receptors on activated T lymphocytes
and is chemotactic for T lymphocytes. IL-1 is also
produced by the Langerhans cell and involved in
antigen presentation and Langerhans cell migration.
Furthermore, IL-1 is capable of inducing other keratinocytes to release or synthesize IL-1 in a paracrine

or even autocrine fashion [67] as well as upregulating

other cytokines including epidermal growth factor,
IL-6, IL-8, and GM-CSF [68]. Thus, the release of IL-1
can lead to amplification of the ongoing immunological process. In addition to its capacity to regulate
other cytokines, IL-1 upregulates cell adhesion molecules on the keratinocyte. In vitro analyses have
demonstrated that IL-1 upregulates ICAM-1 expression on keratinocytes, thereby further contributing
to the maintenance of the inflammatory cells in the
skin.
When analyzing cytokine profiles in the early
phases of the allergic as well as irritant reaction in
mice, Enk and Katz demonstrated that IL-1 is upregulated as early as 15 min following application of an
allergen but not an irritant. Cell depletion studies revealed the Langerhans cell as the cellular source [60].
Furthermore, blocking IL-1 inhibited the elicitation
of the allergic reaction, thereby substantiated by the
importance of IL-1. Similar, injection of recombinant IL-1 in vivo led to the development of a clinical
reaction, indistinguishable from the contact dermatitis reaction. This observation has supported the hypothesis that expression of IL-1 could differentiate
between contact allergic and irritant reactions. However, later studies have indeed found IL-1 in the irritant reaction, though at later time points [56, 57].
Thus, early synthesis of IL-1 seems to be an important initial step in the induction of allergic contact
dermatitis, but is not specific for allergic reactions.

Core Message
Both IL-1 and IL-1 have been found to be
upregulated in the contact irritant reaction.
In murine studies, IL-1 was the first cytokine upregulated and injection of IL-1 in
vivo resulted in clinical eczema indistinguishable from the irritant reaction.

4.6 Irritant-induced TNF-

TNF- was first described as a molecule exhibiting
anti-tumor activity in vivo and in vitro. TNF- is a
highly pleomorphic cytokine [66], produced by a variety of cell types, including T lymphocytes, monocytes, Langerhans cells, fibroblasts, and keratinocytes.
TNF- is synthesized as a 26-kDa pro-peptide. Before secretion the pro-peptide is converted into a 17kDa protein by metalloproteases [69]. In its active
form, TNF- is composed of three 17-kDa subunits.

Mechanisms of Irritant Contact Dermatitis

TNF- exerts its function by binding to specific

cell surface receptors. Two distinct TNF- receptors
are described. TNF-R1 (414 amino acids) has a molecular weight of approximately 5560 kDa and TNFR2 (461 amino acids) is a 75- to 80-kDa receptor.
These receptors have similar extracellular structures
but distinct cytoplasmic domains. The TNF receptors
are expressed on a variety of cells, however mainly
the TNF-R1, which is involved in metabolic alterations, cytokine production, and cell death, is expressed on the keratinocytes [70]. TNF- stimulates
the production of collagenase and prostaglandin E2
by synovial cells and dermal fibroblasts and thus
contributes to inflammation and tissue destruction
in general. TNF- increases both MHC class II antigen expression and upregulates the surface expression of ICAM-1 on keratinocytes [71, 72]. Thus, TNF is an important cytokine involved in the maintenance of inflammatory processes in the skin. The
pro-inflammatory role of TNF- is stressed by its capacity to induce other inflammatory markers, including IL-1, IL-6, and the chemoattractant IL-8
[66].
Finally, it has been demonstrated that blocking
TNF- results in inhibition of Langerhans cell migration towards the local lymph nodes following epicutaneously applied allergens or irritants [73, 74].
The importance of TNF- in irritant contact dermatitis has been further emphasized by studies by Piguet et al. demonstrating that primary irritant reactions to trinitrochlorobenzene (TNCB) could be inhibited in vivo by injection of antibodies to TNF or
recombinant soluble TNF receptors [61]. Thus, TNF seems to be a key player in the induction of irritant
reactions in the skin.
Several irritants exhibit the capacity to upregulate
TNF- in skin. These irritants include dimethylsulfoxide (DMSO), PMA, formaldehyde, phenol, tributylin, and SLS [56, 62, 75]. The list of skin irritants that
upregulate TNF- is still growing, and studies reveal
that this upregulation is also found by application of
allergens to the skin and when analyzing the irritant
capacity of sensitizers, e.g., TNCB, DNTB, and nickel
[61, 62]. Although many irritants upregulate TNF-
in skin, no increase in TNF- expression has been
observed following skin application of benzalkonium chloride [58]. Thus, as previously discussed, different irritants interact or regulate the immune system at different levels.

Chapter 4

Core Message
Several irritants can induce keratinocyte
expression of TNF- both in vitro and in
vivo. The importance of irritant-induced
TNF- is stressed by observations by
Piguet et al. [61], who could block elicitation of irritant reactions by administration
of anti-TNF antibodies.

4.7 Mechanisms of Irritant-induced TNF-

in Keratinocytes
Most previous studies addressing the upregulation of
cytokine expression in skin have focused on protein
measurements often by ELISA. In addition, cytokine mRNA expression has been determined by either Northern blotting or reverse transcriptase polymerase chain reaction (RT-PCR). Increased protein
and mRNA expression has been interpreted as an increase in synthesis of the investigated cytokine. However, increased mRNA stability or other posttranscriptional modifications have hardly been addressed. The importance of such investigations is
stressed by findings that both transcriptional and
translational mechanisms were involved the lipopolysaccharide-induced upregulation of TNF- mRNA
in macrophages [76]. Recently it was determined
whether transcriptional or posttranscriptional
mechanisms are involved in the irritant-induced upregulation of TNF- in keratinocytes [62]. This study
was performed on murine keratinocytes that were
transfected with a chloramphenicol acetyl transferase (CAT) reporter construct containing the fulllength TNF- 5-promoter region. Increased TNF-
promoter activity was indeed observed following in
vitro exposure to the irritants PMA and DMSO,
strongly suggesting that the PMA- and DMSO-induced upregulation of TNF- mRNA in keratinocytes is due to increased transcription of the TNF-
gene. These findings were further substantiated by
the observation that no significant difference in
TNF- mRNA stability was observed between unstimulated and stimulated keratinocytes [62]. It is
generally accepted that the irritant PMA mediates
most of its effects via PKC-dependent signal transduction pathways. Accordingly, it was found that
PMA, as well as the common irritants DMSO and
SLS, induced an increase in TNF- mRNA in keratinocytes via a PKC-dependent signaling pathway
(Fig. 2).

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Steen Lisby, Ole Baadsgaard

Fig. 2. Mechanisms of irritant-induced TNF- in keratinocytes. Irritants (e.g., PMA, DMSO, SLS) upregulate TNF- mRNA
in keratinocytes via a PKC-dependent signaling pathway resulting in increased mRNA transcription. In contrast, nickel
salts mediate their effects by increasing the stability of TNF-

It is known that nickel, in addition to being a frequent contact sensitizer, can act as an irritant in nonsensitized animals. Furthermore, nickel exhibits the
capacity to upregulate TNF- mRNA and protein in
purified keratinocytes. Inhibitors of PKC and of the
cyclic nucleoside-dependent protein kinase were reported not to block this nickel-induced increase in
TNF- mRNA. In addition, this study demonstrated
no increase in TNF- promoter activity following
stimulation with nickel. Of particularly interest was
the finding that nickel stimulation of keratinocytes
in vitro resulted in a pronounced increase in the
stability of TNF- mRNA as compared to unstimulated control cultures [62]. The precise mechanism of
the nickel-induced increased stability of TNF-
mRNA remains unclear. One possibility is modification of peptides binding to an AUUUA-sequence in
the 3-region of the mRNA thereby blocking/inhibiting degradation of the mRNA transcript. Another
possibility is that nickel stimulation could result in
sequestering TNF- mRNA in the ribosomal compartment, thereby stabilizing the mRNA. Independently of the mechanism, the overall result was an increase in the release of biologically active TNF protein.
Thus, when comparing the irritant effect of nickel
in nonsensitized animals with irritants such as
DMSO and PMA, different intracellular signaling
mechanisms are involved in upregulation of TNF-
peptide expression (Fig. 2).

mRNA. Both pathways ultimately lead to increased release of

TNF protein. (DMSO Dimethylsulfoxide, PKC protein kinase C,
PMA phorbol myristate acetate, SLS sodium lauryl sulfate, TNF
tumor necrosis factor)

Core Message
Not all skin irritants induce measurable
TNF-. Furthermore, different signaling
mechanisms have been described, including direct gene activation (transcription)
and stabilization of the TNF- mRNA
(posttranscriptional regulation).

4.7.1 Regulation of the Inflammatory

Milieu Locally in Inflamed Skin
As described in this chapter, an upregulation of proand inflammatory cytokines is present in the irritant
reaction. It is noteworthy that this type of reaction
often tends to exhibit a prolonged course, even despite removal of the irritant exposure. Thus, the clinical reaction may continue for several years. Until recently, no explanation for this phenomenon has been
forwarded. However, data are now available suggesting that elements in the local inflammatory milieu
may actually contribute to the persistence of skin inflammation. Previous, it was shown that autocrine
regulation of IL-1, both IL-1 and IL-1, is present in
vitro [77, 78]. Therefore, a study was enforced to describe whether such autocrine regulation of the proinflammatory cytokine TNF was present in keratinocytes. Indeed, it was found that stimulating keratinocytes with TNF- in vitro led to an increase in

Mechanisms of Irritant Contact Dermatitis

TNF- mRNA expression [79]. This potential, interesting signaling pathway was critically dependent
upon signaling through PKC-dependent pathways
and involved increased gene transcription. Thus, it
was shown that induction of the pro-inflammatory
cytokine TNF-, e.g., by skin irritants, could lead to
induction of an autocrine signaling pathway locally
in the skin, thereby substantiating the inflammatory
reaction and as such contributing to the persistence
of the clinical irritant skin reaction.

Core Message
Skin irritants can induce an inflammatory
milieu, following which further amplification is possible. Today, data exist demonstrating autocrine regulation of both IL-1
and TNF- in keratinocytes.

4.8 Hypothesis of the Immunological

Events Leading to Irritant Contact
Dermatitis
Following application of irritants to the skin, penetration of the stratum corneum is the primary event.
During this, perturbation of the skin barrier occurs.
This further facilitates the penetration of the skin by
the irritant and other external agents. Following penetration of the stratum corneum, the irritant most
likely induces the release of pre-formed IL-1 from
the keratinocytes, and induces the synthesis of several other immunoregulatory keratinocyte-derived cy-

Fig. 3.
Epidermal changes following
exposure to irritants

Chapter 4

tokines (Fig. 3). TNF- in particular seems essential,

because in a murine system injection of antibodies to
TNF in vivo completely blocks the development of irritant reactions [61]. The mechanism of irritant-induced upregulation of TNF- seems to involve increased transcription of the gene; however, irritantinduced stabilization of cytokine mRNA may also
contribute [62]. Next, induction of cell adhesion
molecules such as ICAM-1 on the keratinocytes and
E-selectin on the endothelial cells facilitates the extravasation of inflammatory T lymphocytes to the
skin. This process may be enforced by the release of
the chemoattractant IL-8 by the keratinocytes [80].
During the first 2472 h, an epidermal influx on nonLangerhans cell-derived antigen-presenting cells occurs. In addition, the number of epidermal Langerhans cells decreases and these cells possibly migrate
towards the draining local lymph node. A cellular infiltrate comprised mainly of mononuclear cells, in
particular CD4+ T lymphocytes, is then seen in the
involved skin area. These cells are activated and they
release inflammatory cytokines. In particular, increased levels of IFN- and IL-2 have been observed
[41]. Ultimately, these events lead to the histological
picture of acute irritant contact dermatitis.
The often-observed chronicity of irritant contact
dermatitis is elusive. However, the irritant-induced
inflammation may expose the immune system to immunogenic skin peptides that it does not normally
see. The chronicity may therefore involve presentation of such self-peptides to the immune system resulting in the development of an autoimmune skin
disease. Alternative, the irritant-induced TNF- is
regulated in an autocrine way and thereby involved
in the maintenance of an inflammatory milieu locally in the skin. The resulting irritant contact dermatitis reaction may continue for years.

79

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Steen Lisby, Ole Baadsgaard

Suggested Reading

1. Piguet PF, Grau GE, Hauser C, Vassalli P (1991) Tumor necrosis factor is a critical mediator in hapten-induced irritant and contact hypersensitivity reactions. J Exp Med
173 : 673679
This paper describe in detail the presence and significance
of TNF-a in the contact irritant reaction as well as elicitation of the contact allergic reaction. Using the in situ hybridization technique, the authors directly demonstrate an
important role of the keratinocyte in this induction, thus
implicating the keratinocyte as an important player in the
induction of the contact irritant reaction in skin.

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