MyD88 and Src Are Differentially Regulated in Kupffer Cells of Males and Proestrus Females Following Hypoxias

Abstract

Hypoxia produces sex dimorphic immune responses in males and proestrus females. Because Kupffer cells are the major source of proinflammatory cytokines, studies were conducted to discern IL-6 production in mouse Kupffer cells following hypoxia. Hypoxia enhances TLR4 expression in Kupffer cells irrespective of sex. However, MyD88 and Src expression in Kupffer cells decreased significantly after hypoxia in proestrus females, whereas Src protein expression and phosphorylation increased in males in concurrence with differences in IL-6 production. 17β-Estradiol administration elevated MyD88 and Src expression in males to levels in normoxic proestrus females. Administration of Src inhibitor in hypoxic males prevented increased IL-6 production. Thus, differential regulation of MyD88 and Src in males and females plays an important role in sex-specific immune response following hypoxia.

Cytosolic phospholipase A2induction and prostaglandin E2release by interleukin-1β via the myeloid differentiation factor 88-dependent pathway and cooperation of p300, Akt, and NF-κB activity in human rheumatoid arthritis synovial fibroblasts

“…The Toll/IL‐1 receptor domain, MyD88 recruitment, and subsequent downstream signaling are critical to the production of mediators of inflammation (21). When we examined whether MyD88 participated in IL‐1β–induced responses, we observed that transfection of RASFs with MyD88 siRNA significantly reduced MyD88 protein expression and IL‐1β–induced cPLA 2 expression (Figure 2A).…”

Sex differences in hippocampal cytokine networks after systemic immune challenge

“…Coupling of immune-related receptors and intracellular signaling is critical to subsequent responses, and many studies show sex-specificity of these pathways. For example, males show higher numbers of Toll-like-receptor (TLR) 4, and differential regulation of downstream signaling pathways [66][67][68]. Given that LPS activates immune responses via interactions with TLR4, this is a central candidate for sex differences in rapid effects of LPS.…”

(Putative) sex differences in neuroimmune modulation of memory

“…like receptors (TLRs) and their subsequent cytokine response (Scotland et al, 2011;vom Steeg and Klein, 2016). Whereas males show higher numbers of TLR4 receptors (Roberts et al, 2013), females show stronger activation of intracellular signaling pathways (Zheng et al, 2006) and stronger cytokine response after TLR7 stimulation (Bergh€ ofer et al, 2006), potentially mediating divergent responses of males and females. Strikingly, there are consistent sex differences in T-cell activation following an immune response.…”

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