Gender difference in granulocyte dynamics and apoptosis and the role of IL-18 during endotoxin-induced systemic inflammation.

Delayed granulocyte apoptosis is implicated in persistent inflammation. Although it is known that males develop sepsis more easily than females, the mechanism for this is not fully understood. Serum IL-18 levels correspond to severity of systemic inflammation. The purpose of this study was to elucidate gender differences and the effects of IL-18 on granulocyte dynamics and apoptosis. Male and female wild-type (WT) and IL-18 knockout (KO) mice were injected intraperitoneally with LPS. Bone marrow cells, peripheral blood, and peritoneal cells were then collected at different times up to 24 h after injection. Apoptosis was assessed by annexin V staining using three-color flow cytometry with differentiated granulocyte-specific Gr-1, B-lymphocyte-specific B220, and macrophage-specific F4/80 antibodies. Male WT mice were more susceptible to endotoxin than female WT mice (survival rate, 41% in male WT and 84% in female WT). Male WT mice showed stronger responses than females in myeloid differentiation, release of myeloid cells from the bone marrow into the periphery, and migration into the inflammatory peritoneal cavity. Male mice also showed greater inhibition of granulocyte apoptosis in the peritoneal cavity, which might also contribute to the higher numbers of those cells present. A comparison between WT and KO mice revealed that the gender difference in these myeloid cells/granulocytes' behaviors was independent of endogenous IL-18. Nevertheless, levels of IL-18 in the blood of WT mice were significantly higher in males than in females after intraperitoneal LPS, and the survival rate was significantly higher in KO mice compared with WT mice only in males. This indicates that endogenous IL-18 production decreases survival only in males. Thus, excessive myeloid/granulocyte immunity independent of IL-18 and other IL-18-dependent life-threatening factors in males should be taken into account as therapeutic targets during systemic inflammatory states.