Sex differences in IL-10’s anti-inflammatory function: greater STAT3 activation and stronger inhibition of TNF-α production in male blood leukocytes ex vivo

Abstract

Interleukin-10 (IL-10) inhibits pro-inflammatory cytokine production in blood leukocytes - an effect mediated by signal transducer and activator of transcription 3 (STAT3) activation. To examine potential sex-based differences in IL-10's anti-inflammatory function, we treated whole blood from healthy males and females (n=16 each; age: 28±6 years; body mass index: 23.5±2.3 kg/m2) with increasing concentrations of IL-10 (1-100 ng/mL) and quantified changes in phosphorylated STAT3 (pSTAT3) in CD14+ monocytes and CD4+ lymphocytes via flow cytometry. In parallel, liposaccharide (LPS)-stimulated whole-blood cultures were used to assess sex-based differences in IL-10's ability to inhibit tumour necrosis factor (TNF)-α production. IL-10 concentration-dependently increased pSTAT3 mean fluorescent intensity (MFI) in CD14+ and CD4+ cells (main effects of concentration, P<0.01) with males exhibiting larger changes in pSTAT3 MFI in both cell types (main effects of sex, P<0.01). Accordingly, IL-10-mediated inhibition of TNF-α production was more pronounced in males (main effect of sex, P<0.01) with changes in other monocyte-derived cytokines (IL-1b, IL-1RA, IL-15) also supporting a sexual dimorphism in IL-10 action (P<0.05). These sex-based differences were not explained by differences in circulating plasma IL-10 concentrations, basal IL-10 receptor expression in unstimulated CD14+ and CD4+ cells, nor the basal expression of IL-10 signaling proteins (STAT3, SHIP1, p38 MAPK) in unstimulated peripheral blood mononuclear cells. We conclude that IL-10's anti-inflammatory function differs between male and female blood leukocytes ex vivo. This sexual dimorphism should be considered in future work investigating IL-10's anti-inflammatory action in humans as it may represent a mechanism contributing to sex differences in overall immune function.

Influence of IL10 and TGFB1 Promoter Polymorphisms on Serum Cytokine Levels in Development and Severity of RA

“…Our current study confirms the increased IL-10 levels in RA cases on a systemic level. We should note that we limited our study to women in accordance with the known prevalence of RA among women, more than 3 folds, previously reported sex differences in IL-10 production and its anti-inflammatory properties [ 15 , 16 ].…”

Female rats have a different healing phenotype than males after anterior cruciate ligament rupture with no intervention

“…In females, an increase in IL-4 was accompanied by a decrease in IL-10, while a reduction in IL-4 in males was accompanied by a 6-fold increase in IL-10. Interestingly, sexual dimorphism was recently described for IL-10's anti-inflammatory action toward leukocytes, and for IL-4-induced monocyte polarization (24,25). It is possible that the contrasting plasma cytokine responses we observed reflect differences in the cytokine responsiveness of leukocytes in males and females, and that this may underlie subtle changes in the pattern of inflammatory cell mobilization and recruitment to the site of injury.…”

A Chinese classical prescription Maimendong decoction in treatment of pulmonary fibrosis: an overview

“…Therefore, reducing levels of inflammatory cytokines is an effective strategy for treating PF. IL-10 exerts anti-inflammatory effects by inhibiting TNF-α production at the transcriptional level ( Islam et al, 2022 ). Studies have shown that MMDD can reduce alveolar inflammation and PF in rats, potentially through the decrease in IL-10 expression and inhibition of lung TNF-α, transforming growth factor-β1 (TGF-β1), platelet-derived factor (PDGF), and connective tissue growth factor (CTGF) ( Du, 2015 ).…”