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

Chia-Chang Chuang,Chiou-Feng Lin,A-Ming Huang,Pui-Ching Choi,Chi-Yun Wang,Po-Chin Tseng,Wen-Teng Chang,Chi-Chung Chen,Yin-Ching Chuang,Lien-I Hor

doi:10.1186/1471-2172-11-50

Abstract

BackgroundPatients 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.ResultsMIF 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.ConclusionsWe 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.

Highlights

Patients infected with Vibrio vulnificus (V. vulnificus) show severe inflammatory responses characterised by the upregulation of proinflammatory cytokines
Because our results showed that migration inhibitory factor (MIF) increased earlier than IL-6 and tumour necrosis factor (TNF)-a, we hypothesised that the early presence of serum MIF acts as an upstream enhancer or modulator of other proinflammatory cytokines, especially IL-6, during V. vulnificus infection
MIF was an upstream modulator of IL-6, IL-8, and TNF-a We examined the effect of MIF inhibition on the production of the proinflammatory cytokines IL-6, IL-8, and TNF-a in V. vulnificus-infected human whole blood and isolated peripheral blood mononuclear cells (PBMCs)

Summary

Introduction

Patients infected with Vibrio vulnificus (V. vulnificus) show severe inflammatory responses characterised by the upregulation of proinflammatory cytokines. Whether MIF regulates responses to V. vulnificus infection and the actual mechanism by which V. vulnificus initiates these MIF-modulated proinflammatory cytokines remain unclear. Macrophage migration inhibitory factor (MIF), an important proinflammatory cytokine, is a critical mediator of innate immunity and is implicated in the pathogenesis of sepsis [8,9]. MIF-deficient macrophages are hypo-responsive to stimulation by LPS and Gram-negative bacteria because of a defect in Toll-like receptor 4 signalling and protein expression [15]. These findings show that MIF is important in innate immunity and provide a rationale for the development of an anti-MIF strategy to treat patients with Gram-negative septic shock. The importance of ISO-1-mediated inhibition of the MIF catalytic site in the suppression of cytokine proinflammatory activity suggests that the effect of ISO-1 requires endogenous MIF

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