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IL-17 and IFN- Mediate the Elicitation of Contact Hypersensitivity Responses by Different Mechanisms and Both Are Required for Optimal Responses¹

Department of Dermatology, University of Alabama, Birmingham, Alabama 35294

Hapten-induced contact hypersensitivity (CHS) in the skin is a delayed type cellular immune response that can be mediated by CD8⁺ T cells that produce IFN- or IL-17. However, mechanisms for these cytokines in the elicitation of CHS remain to be fully elucidated. In this study, we show that adoptive transfer of CHS with hapten-primed wild-type (WT) CD8⁺ T cells is reduced in IFN-R^–/– or IL-17R^–/– mice compared with WT controls. The infiltration of granulocytes and macrophages in the hapten challenged skin of IL-17R^–/– recipients is significantly reduced whereas it is less affected in IFN-R^–/– recipients although CD8⁺ T cell infiltration is inhibited in both recipients. In contrast, the activity of reactive oxidative species is significantly inhibited in IFN-R^–/– but is less affected in IL-17R^–/– recipients. Further analysis reveals that the expression of chemokines and cytokines is differentially regulated in the hapten-challenged skin of IFN-R^–/– or IL-17R^–/– recipients compared with WT controls. Interestingly, injection of rIL-17 in the skin induces inflammation with a high level of leukocyte infiltration whereas injection of IFN- induces inflammation with a high level of reactive oxidative species. Moreover, neutralization of IL-17 in IFN-R^–/– or IFN- in IL-17R^–/– mice further suppresses the adoptive transfer of CHS by hapten-primed WT CD8⁺ T cells. The study demonstrates that IFN- and IL-17 mediate the elicitation of CHS by different mechanisms and that both cytokines are required for optimal responses. This outcome improves understanding of pathogenesis and provides new insights into therapeutic strategies for CHS.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This publication was made possible by AR46256 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and AI071041 from the National Institute of Allergy and Infectious Diseases (to H.X.). This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program Grant No. C06 RR 15490 from the National Center for Research Resources, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Hui Xu, VH566B, 1670 University Boulevard, University of Alabama, Birmingham, AL 35294. E-mail address: xuhui{at}uab.edu

³ Abbreviations used in this paper: CHS, contact hypersensitivity; ROS, reactive oxidative species; WT, wild type; iNOS, inducible nitric oxide synthase; DNFB, dinitrofluorobenzene; DNBS, dinitrobenzenesulfonic acid, sodium salt; BM-DC, bone marrow-derived dendritic cell; MPO, myeloperoxidase.

⁴ The online version of this article contains supplemental material.