Rethinking the role of tumour necrosis factor-alpha in ultraviolet (UV) B-induced immunosuppression: altered immune response in UV-irradiated TNFR1R2gene-targeted mutant mice

Background Ultraviolet (UV) B-induced immunosuppression, implicated in the pathogenesis of skin cancers, is postulated to be mediated in part by cis-u rocanic acid (cis-UCA) via tumour necrosis factor (TNF)-alpha. TNF-alpha pr oduces morphological changes in Langerhans cells indistinguishable from tho se induced by UVB exposure and antibodies against TNF-alpha have been demon strated to inhibit UVB-induced immunosuppression in vivo. Objectives To clarify further the role of TNF-alpha in UVB-induced immunosu ppression and in cis-UCA immunosuppression. Methods We performed a contact hypersensitivity (CHS) assay on gene-targete d mutant mice (TNFR1R2-/-) lacking genes for both receptors (p55 and p75) f or TNF-alpha. Mice were either irradiated with UVB or injected intradermall y with cis-UCA, sensitized with 2,4-dinitrofluorobenzene, challenged on the ears and the response was measured. Results The TNFR1R2-/- mice showed hyporesponsiveness in the CHS response c ompared with wild-type (P < 0.001), confirming the proinflammatory role of TNF-alpha. However, significant suppression of CHS was seen after irradiati on and after cis-UCA injection in both locally (sensitization on irradiated site; P < 0.05) and systemically (sensitization on non-irradiated site; P < 0.05) sensitized wild-type and gene-targeted mice. Conclusions These results demonstrate that TNF-alpha signalling is only par tially involved in UVB-induced immunosuppression and does not play a major part in the cis-UCA immunosuppression mechanism.