Macrophage migration inhibitory factor regulates interleukin-6 production by facilitating nuclear factor-kappa B activation during Vibrio vulnificus infection
- Equal contributors
1 Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
2 Department of Emergency Medicine, National Cheng Kung University Hospital, Tainan 701, Taiwan
3 Department of Medical Research, Chi Mei Medical Center, Tainan County 710, Taiwan
4 Department of Biological Science and Technology, Chung Hwa University of Medical Technology, Tainan County 717, Taiwan
5 Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
6 Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
BMC Immunology 2010, 11:50 doi:10.1186/1471-2172-11-50Published: 12 October 2010
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.
MIF increased inflammation during V. vulnificus infection in vivo. In V. vulnificus-infected mice, MIF was produced earlier than tumour necrosis factor (TNF)-α 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-α 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-α production by V. vulnificus infection was mediated via the NF-κB- and p38 MAPK-regulated pathways but not via the Akt pathway. ISO-1-treated human peripheral blood cells showed lower V. vulnificus-induced NF-κB activation, IL-6 mRNA expression, and IκB phosphorylation, but they did not show lower p38 MAPK activation.
We conclude that MIF regulates V. vulnificus-induced IL-6 production via NF-κB activation and that p38 MAPK activation in V. vulnificus infection is not MIF dependent.