The Hardening Phenomenon in Irritant Contact Dermatitis: Cosmetic Implications

By: Howard I. Maibach, MD, University of California School of Medicine, San Francisco and Shannon A. Watkins, MD, Yale New Haven Hospital

Posted: October 30, 2009, from the November 2009 issue of Cosmetics & Toiletries.

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Immunologic Changes with Hardening
de Jongh et al. recently showed an altered local expression of multiple cytokines and inflammatory mediators with repeated versus single irritant insults to the skin, and hardening was correlated with these changes in the inflammatory profile of the skin.¹² The balance between the cytokines IL-1α and IL1-RA may be an important factor in determining the inflammatory response in hardened skin.

IL1-α is a well-known pro-inflammatory mediator whose effects are counteracted by the anti-inflammatory cytokine IL-1RA. The study by de Jongh et al. showed that IL1-α was increased after a single irritant exposure, while IL-1RA was increased after repeated irritation. The ratio of IL-1RA/IL-1α was increased after repetitive irritation but not after single irritation, suggesting that with repetitive irritation, anti-inflammatory mechanisms come into play to suppress the early pro-inflammatory responses. This altered ratio could be one explanation for the hardening response.¹² Granulocyte colony-stimulating factor (G-CSF), which traditionally is considered pro-inflammatory, recently was shown to have anti-inflammatory properties as well,¹³ and may also play an anti-inflammatory role and contribute to hardening in the skin after repeated irritation.¹²

Discussion and Conclusions
As mentioned, multiple extrinsic and intrinsic factors influence human irritancy and the mechanisms and predisposing factors determining whether an individual adapts to irritant exposure or develops chronic ICD require investigation. Genetics are an important intrinsic factor. Certain IL1 genotypes have been associated with higher levels of the pro-inflammatory IL-1α and higher IL-1α/IL-1RA ratios, suggesting certain IL1 genotypes may predispose to skin irritation while others may protect against it.¹⁴ This suggests that altered cytokine expression may be responsible for differences in the inflammatory response and inter-individual differences in skin hardening.

Another theory to be explored is whether there is irritant cross-reactivity with hardening in irritant contact dermatitis. In 1967, McOsker showed evidence of this when animals that accommodated to 0.25% alkyl benzene sulfonate were also found to resist irritation by other irritants.⁷ The specificity of hardening in humans, however, remains to be investigated.

Other possibilities for research include further exploration of physical changes of the epidermis with the emergence of hardening. Ceramide 1, an important lipid in SC barrier function, has been shown to up-regulated with hardening.⁸ It also may be interesting to explore the expression of other stratum corneum molecules such as filaggrin.⁶ Further characterization of the cytokine profile present in normal versus hardened skin, and an investigation of global changes in the immunologic profile observed with hardening may also prove enlightening.