IL-10 fails to inhibit the production of IL-18 in response to inflammatory stimuli.

IL-10 is an inhibitor of the production of pro-inflammatory cytokines such as IL-12 and IL-1beta, but it is not known whether it can inhibit the production of IL-18. Therefore, a variety of in vivo and in vitro models were used to determine whether IL-10 is an inhibitor of IL-18 production. Infection of IL-10-/- mice with Toxoplasma gondii results in increased levels of IL-12 in the serum and in recall responses compared to wild type (WT) mice. Surprisingly, although infection resulted in increased levels of IL-18 in serum, there were no differences between WT and IL-10-/- mice. Moreover, splenocytes from infected WT and IL-10-/- mice produced similar levels of IL-18 and addition of exogenous IL-10 did not inhibit their production of IL-18. To address whether endogenous IL-18 inhibitors were masking increased IL-18 production in the IL-10-/- mice, expression of IL-18 binding protein was examined using RT-PCR. Although infection leads to increased expression of IL-18BP mRNA, no difference was seen between WT and IL-10-/- mice. In addition, splenocytes from IL-10-/- mice produced elevated levels of nitric oxide (NO) compared to WT mice, and NO has been shown to inhibit activity of interleukin-1 converting enzyme (ICE), which is required for IL-18 production. However, the addition of an inhibitor of NO production did not alter the levels of IL-18 produced. Finally, analysis of the levels of cytokine mRNA of macrophages stimulated with LPS and IFN-gamma revealed that although IL-10 is a potent inhibitor of IL-12 mRNA accumulation, it did not inhibit IL-1beta or IL-18. Together, these data indicate that IL-10 is not an inhibitor of the production of IL-18.