Sex differences in the pro-inflammatory cytokine response to endotoxin unfold invivo but not ex vivo in healthy humans

Clinical data indicate that inflammatory responses differ across sexes, but the mechanisms remain elusive. Herein, we assessed invivo and ex vivo cytokine responses to bacterial endotoxin in healthy men and women to elucidate the role of systemic and cellular factors underlying sex differences in inflammatory responses. Participants received an i.v. injection of low-dose endotoxin (0.4ng/kg body mass), and plasma TNF- and IL-6 responses were analyzed over a period of 6h. In parallel, ex vivo cytokine production was measured in endotoxin-stimulated blood samples obtained immediately before invivo endotoxin administration. As glucocorticoids (GCs) play an important role in the negative feedback regulation of the inflammatory response, we additionally analyzed plasma cortisol concentrations and ex vivo GC sensitivity of cytokine production. Results revealed greater invivo pro-inflammatory responses in women compared with men, with significantly higher increases in plasma TNF- and IL-6 concentrations. In addition, the endotoxin-induced rise in plasma cortisol was more pronounced in women. In contrast, no sex differences in ex vivo cytokine production and GC sensitivity were observed. Together, these findings demonstrate major differences in invivo and ex vivo responses to endotoxin and underscore the importance of systemic factors underlying sex differences in the inflammatory response.