Macrophage migration inhibitory factor regulates interleukin-6 production by facilitating nuclear factor-kappa B activation during Vibrio vulnificus infection

Background: Patients infected with Vibrio vulnificus (V. vulnificus) show severe inflammatory responses characterised by the upregulation of proinflammatory cytokines. Macrophage migration inhibitory factor (MIF), an upstream proinflammatory regulator, increases the inflammation caused by sepsis. Whether MIF regulates responses to V. vulnificus infection and the actual mechanism by which V. vulnificus initiates these MIF-modulated proinflammatory cytokines remain unclear. Results: MIF increased inflammation during V. vulnificus infection in vivo. In V. vulnificus-infected mice, MIF was produced earlier than tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 and was expressed in a time-dependent manner. ISO-1 ((S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester), a small-molecule inhibitor of MIF, significantly decreased IL-6, IL-8, and TNF-alpha production in a time-and dose-dependent manner in human peripheral blood cells infected with V. vulnificus. The induction of IL-6, IL-8, and TNF-alpha production by V. vulnificus infection was mediated via the NF-kappa B- and p38 MAPK-regulated pathways but not via the Akt pathway. ISO-1-treated human peripheral blood cells showed lower V. vulnificus-induced NF-kappa B activation, IL-6 mRNA expression, and I kappa B phosphorylation, but they did not show lower p38 MAPK activation. Conclusions: We conclude that MIF regulates V. vulnificus-induced IL-6 production via NF-kappa B activation and that p38 MAPK activation in V. vulnificus infection is not MIF dependent.