EFFECTS OF INTERLEUKIN-10 ON HUMAN PERIPHERAL-BLOOD MONONUCLEAR CELL RESPONSES TO CRYPTOCOCCUS-NEOFORMANS, CANDIDA-ALBICANS, AND LIPOPOLYSACCHARIDE

Deactivation of mononuclear phagocytes is critical to limit the inflam matory response but can be detrimental in the face of progressive infe ction. We compared the effects of the deactivating cytokine interleuki n 10 (IL-10) on human peripheral blood mononuclear cell (PBMC) respons es to lipopolysaccharide (LPS), Cryptococcus neoformans, and Candida a lbicans. IL-10 effected dose-dependent inhibition of tumor necrosis fa ctor alpha (TNF-alpha) release in PBMC stimulated by LPS and C. neofor mans, with significant inhibition seen with 0.1 U/ml and greater than 90% inhibition noted with 10 U/ml. In contrast, even at doses as high as 100 U/ml, IL-10 inhibited TNF-alpha release in response to C. albic ans by only 50%. IL-10 profoundly inhibited release of IL-1 beta from PBMC stimulated by all three stimuli. TNF-alpha mRNA and release was i nhibited even if IL-10 was added up to 8 h after cryptococcal stimulat ion. In contrast, inhibition of IL-1 beta mRNA was of lesser magnitude and occurred only when IL-10 was added within 2 h of cryptococcal sti mulation. IL-10 inhibited translocation of NF-kappa D in response to L PS but not the fungal stimuli. All three stimuli induced IL-10 product ion in PBMC, although over 10-fold less IL-10 was released in response to C. neoformans compared with LPS and C. albicans. Thus, while IL-10 has deactivating effects on PBMC responses to all three stimuli, disp arate stimulus- and response-specific patterns of deactivation are see n. Inhibition by IL-10 of proinflammatory cytokine release appears to occur at the level of gene transcription for TNF-alpha and both transc riptionally and posttranscriptionally for IL-1 beta.