Effects of interleukin-10 on human peripheral blood mononuclear cell responses to Cryptococcus neoformans, Candida albicans, and lipopolysaccharide

Abstract

Deactivation of mononuclear phagocytes is critical to limit the inflammatory response but can be detrimental in the face of progressive infection. We compared the effects of the deactivating cytokine interleukin 10 (IL-10) on human peripheral blood mononuclear cell (PBMC) responses to lipopolysaccharide (LPS), Cryptococcus neoformans, and Candida albicans. IL-10 effected dose-dependent inhibition of tumor necrosis factor alpha (TNF-␣) release in PBMC stimulated by LPS and C. neoformans, 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-␣ release in response to C. albicans by only 50%. IL-10 profoundly inhibited release of IL-1␤ from PBMC stimulated by all three stimuli. TNF-␣ mRNA and release was inhibited even if IL-10 was added up to 8 h after cryptococcal stimulation. In contrast, inhibition of IL-1␤ mRNA was of lesser magnitude and occurred only when IL-10 was added within 2 h of cryptococcal stimulation. IL-10 inhibited translocation of NF-B in response to LPS but not the fungal stimuli. All three stimuli induced IL-10 production 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, disparate stimulus-and response-specific patterns of deactivation are seen. Inhibition by IL-10 of proinflammatory cytokine release appears to occur at the level of gene transcription for TNF-␣ and both transcriptionally and posttranscriptionally for IL-1␤.

Regulatory role of exogenous IL-10 in the development of immune response versus Cryptococcus neoformans

“…One of the critical roles of IL-10 appears to be a powerful modulator of proinflammatory cytokine secretion in response to C. neoformans [18,25]. Therefore, it seems likely that pre-existing IL-10 might be a candidate in stressing both the dampening of the inflammatory process mediated by capsular material of C. neoformans and the inhibition of development of cell-mediated immunity as evidenced in AIDS patients with cryptococcosis [26].…”

Assessing the virulence ofCryptococcus neoformanscausing meningitis in HIV infected and uninfected patients in Vietnam

“…We measured the TNF-α:IL-10 ratio as a proxy for the relationship between a Th-1 and a Th-2 response 25 . From day 7 to day 14 days post-infection, the TNF-α:IL-10 ratio decreased by a factor of 0.78 in mice infected with ST5 isolates, while those infected with non-ST5 strains exhibited an increase in the ratio of 1.25-fold.…”

Effect of Interleukin-10 on Lipopolysaccahride/Interferon-γ-Induced ChemokineMigGene Expression

“…Repeated AU-rich sequence elements (AREs) in the 3'-untranslated region (3'-UTR) of several mRNAs have been shown to be responsible for a short mRNA half-life (32)(33)(34). Moreover, mRNAs encoding TNF-α, IL-1α, IL-1β, and GM-CSF, and the chemokine genes KC, MIP-1α, MIP-1β, and IL-8 have all been reported to be destabilized in IL-10-treated cells (8,10,11, 16,35,36). A common feature of all of these mRNAs is the presence of multiple clusters of AU-rich sequences in the 3'UTR of their mRNAs.…”