Evidence indicates that the testis possesses a reduced capacity to mount inflammatory and rejection responses, which undoubtedly contributes to the ongoing survival of the highly immunogenic germ cells. The contribution of local cytokine expression to this condition was investigated in adult male rats treated with lipopolysaccharide to induce inflammation. Cytokine mRNA and protein expression were determined in tissue extracts and fluids by Northern blot analysis, quantitative PCR, or RNAse protection assay and specific ELISAs. Testicular expression of the proinflammatory cytokines, interleukin (IL)-1beta and tumor necrosis factor-alpha was considerably attenuated compared with the liver (control tissue); in contrast, the testicular IL-6 response was enhanced. Expression of IL-10, a type 2 immunoregulatory cytokine, was similar in both testis and liver, whereas the immunoregulatory/anti-inflammatory cytokines transforming growth factor-beta(1) and activin A were constitutively elevated in both normal and inflamed testes. The IL-1beta and transforming growth factor-beta(1) proteins were present principally in their latent (inactive) forms, indicating that enzymic processing is an important control mechanism for these two cytokines within the testis. These data indicate that inflammatory and regulatory cytokine activity is regulated at both transcriptional and posttranslational levels in a testis-specific manner. It is concluded that a novel pattern of suppression of proinflammatory cytokine responses and normal or elevated expression of immunoregulatory cytokines may be responsible for reduced inflammatory responses and enhanced graft survival in the testis. These data have important implications for the understanding and treatment of male autoimmune infertility, testicular inflammation. and carcinogenesis.