Ultraviolet B-Induced Suppression of Immune Responses in Interleukin-4±/±Mice: Relationship to Dermal Mast Cells Prue H. Hart, Michele A. Grimbaldeston, Aleksandra Jaksic, Joy E. Tan,* Georgina J. Swift, Emma K. Hosszu, Gary M. Halliday,* and John J. Finlay-Jones Department of Microbiology and Infectious Diseases, School of Medicine, Flinders University, Adelaide, Australia; *Department of Medicine (Dermatology), University of Sydney, Australia Ultraviolet B radiation is immunosuppressive by multiple mechanisms. In interleukin-4±/±mice, ultraviolet B radiation was not able to suppress delayed-type hypersensitivity or contact hypersensi- tivity responses when the sensitizing antigen was applied to nonirradiated sites. In contrast, ultraviolet B signi®cantly suppressed contact hypersensitivity responses to haptens applied to irradiated sites in interleukin-4±/±mice. In mast cell depleted Wf/Wf mice, ultraviolet B radiation also signi®cantly sup- pressed contact hypersensitivity responses to sensitiz- ing antigens applied to irradiated but not to unirradiated sites. In both interleukin-4±/±mice and Wf/Wf mice, the mast cell product, histamine, was immunosuppressive implicating mast cells as the dysfunctional cell in interleukin-4±/±mice. The pre- valence of dermal mast cells was similar in wild-type and interleukin-4±/±mice. Dermal mast cells of interleukin-4±/±mice, however, express very low levels of c-kit and did not signi®cantly degranulate in response to ultraviolet B. Ultraviolet radiation induced signi®cant and similar levels of serum inter- leukin-10 in wild-type and interleukin-4±/±mice. We conclude that interleukin-4 indirectly affects ultravio- let B suppression of contact hypersensitivity and delayed-type hypersensitivity responses to sensitizing antigens applied at sites other than those irradiated by providing a critical differentiative signal for der- mal mast cells. This study further emphasizes the central role of mast cells in the initial processes by which ultraviolet B radiation is immunomodulatory for immune responses to sensitizing antigens applied to nonirradiated sites. Key words: cis-urocanic acid/c- kit/dermal mast cells/histamine/interleukin-4±/± mice/ serum interleukin-10/ultraviolet B. J Invest Dermatol 114:508±513, 2000 C ytokines, in particular keratinocyte-derived cyto- kines, have been implicated in the mechanisms by which ultraviolet (UV) B radiation (290±320nm) can suppress immune responses in both humans and experimental animals (for review: Ullrich, 1995); interleukin (IL)-10 and tumor necrosis factor (TNF)-a are the two cytokines most strongly implicated in signaling the immunosup- pressive effects of UVB. Furthermore, IL-10 and TNF-a may be produced by additional cells. TNF-a production has been reported from mast cells (Walsh, 1995) and ®broblasts (De Kossodo et al, 1995) after UVB irradiation. With respect to IL-10, immunohis- tochemical analysis of UVB-irradiated skin and functional analysis of isolated cell populations have implicated both epidermal and dermal cells, including macrophages, as signi®cant and relevant producers after UVB irradiation (Ullrich, 1994; Kang et al, 1998). The importance and relevance of the different immunosuppres- sive cytokines depends on the immune response investigated and whether the sensitizing antigen is applied to an irradiated (local model) or nonirradiated (systemic model) site. Many studies have suggested that IL-10 production is critical to the suppression by UVB of delayed-type hypersensitivity (DTH) responses. In support, in IL-10±/±mice, UVB suppressed contact hypersensitiv- ity (CHS) responses but was unable to suppress DTH responses; in both models the antigen (contact sensitizer or alloantigen, respectively)wasappliedatanonirradiatedsite(Beissert etal,1996). An involvement of TNF in UVB-induced immunosuppression whereby hapten or antigen is applied to the irradiated site was suggested in genetic studies in which susceptibility to UVB- induced immunomodulation was linked to polymorphisms at a locus within the murine major histocompatibility complex (YoshikawaandStreilein,1990;Vincek etal,1993).Morerecently, this UVB susceptibility gene has been mapped within the Bat5 and H-2D segment of mouse chromosome 17, a region of nine genes including TNF-a (Handel-Fernandez et al, 1999). In studies of UVB-induced suppression of CHS responses to sensitizers applied to nonirradiated sites in mice, the product of the Uvs1 gene has been implicated (Noonan and Hoffman, 1994a,b). In studies of TNF±/± and TNF receptor ±/±mice, and in BALB/C and C57BL/6 mice administered a neutralizing anti-TNF antibody, we have similarly found that TNF is critical only to UVB-induced suppression of CHS responses to haptens applied to irradiated sites (Hart et al, 1998b). This result is not surprising because TNF is important for Langerhans cell migration to draining lymph nodes (Cumberbatch and Kimber, 1992). The participation of IL-4, a type 2 cytokine such as IL-10, in UVBbiologiceffectshasbeenlesswellanalyzed,perhapsbecauseit is not a product of keratinocytes. Increased IL-4 production by ManuscriptreceivedJuly12,1999;revisedDecember13,1999;accepted for publication December 13, 1999. Reprint requests to: Dr. Prue Hart, Department of Microbiology & Infectious Diseases, School of Medicine, Flinders University, GPO Box 2100, Adelaide, Australia 5001. Email:prue.hart@¯inders.edu.au Abbreviations: CHS, contact hypersensitivity; SCF, stem cell factor; TNCB, 2,4,6-trinitrochlorobenzene. 0022-202X/00/$15.00 ´ Copyright # 2000 by The Society for Investigative Dermatology, Inc. 508