Of reported occupational injury associated with workman's compensation, contact dermatitis ranks second most prevalent over all. Contact dermatitis is divided into two main manifestations, that of immunological origin (allergic) where T Cells are involved, or non- immunological origin (irritant) where immune memory does not play a role. While irritants may cause overt damage to the skin, both types of dermatitis produce very similar inflammatory responses. Contact sensitizers elicit different cytokine/chemokine profiles as compared to irritants in skin, yet it is not known if specific cytokines are associated with irritant type or strength. Additionally, inflammatory cytokines are known to be closely involved in skin healing, and modulation of specific cytokines by specific irritants could exacerbate skin damage contributing to increased irritancy. If specific cytokines can be associated with irritancy, this may be of significant predictive value when judging the irritancy potential of a chemical, or the response of an individual to irritant exposure. Interestingly JP-8 jet fuel, which is non-corrosive yet causes severe irritant dermatitis, decreases the expression of the inflammatory cytokine IL-6 in exposed skin. Because IL-6 is closely associated with skin healing, the hypothesis is proposed that chemically induced modulation of skin IL-6 levels contributes to severity of dermatitis. Two specific aims are proposed. The first specific aim will investigate whether there is a direct link between the skin expression of this cytokine and damage caused by a chemical irritant. To investigate this IL-6 deficient and wild type C57 mice will be exposed to the irritants JP8 jet fuel, as well as the well characterized irritants SLS, BKC, and acetone as a control. Skin samples will be collected after 1, 3, 5, and 7 days of exposure, and will be assessed for IL-6, IL- 6R, CEBP and SOCS3 mRNA and protein Assessment of overt damage will be determined by visualization of dermatoses, histopathology, and immunohistology. The second specific aim will investigate possible protective effects of treatment with exogenous or endogenous IL-6. Treatment with exogenous IL-6 will involve the direct intradermal injection of rmIL-6 in skin of C57 or IL-6KO mice. Augmentation of endogenous IL-6 will be investigate through the use of the a transgenic mouse model that overexpresses epidermally derived cytokine (Tg(Il6)1Efu). Both of these models will be exposed to irritants as described. Dermatitis will be assessed as described above, as will gene expression for IL-6R, CEBP and SOCS3 which are convenient markers of IL-6 receptor activation. If the hypothesis of this proposal is correct, IL-6 could prove to be a useful marker in determining irritancy potential of a chemical, as well as provide the rational for IL-6 based therapies that may find use in the prophylaxis or treatment of occupational dermatitis.

Public Health Relevance: Disorders of the skin are very common in the work place and of reported occupational injury associated with workman's compensation, contact dermatitis ranks second most prevalent over all. Interleukin 6 is a cytokine produced in skin that is closely associated with healing, and certain irritant chemicals such as JP8 jet fuel, can decrease the amount of this factor in the skin. Determining how interleukin 6 is involved in skin protection from chemical irritants will aid in prediction of a chemical's irritancy potential, may help identify individuals who are susceptible to irritant dermatitis, and could eventually result in the development of therapies for dermatitis based on this cytokine.

R03OH009662

2009-07-01

2011-06-30