Macrophage migration inhibitory factor stimulates interleukin‐17 expression and production in lymph node cells

Abstract

Summary Interleukin (IL)‐17 is a pro‐inflammatory cytokine produced by recently described T helper type 17 (Th17) cells, which have critical role in immunity to extracellular bacteria and the pathogenesis of several autoimmune disorders. IL‐6 and transforming growth factor (TGF)‐β are crucial for the generation of Th17 cells in mice, while the production of IL‐17 is supported by various cytokines, including IL‐23, IL‐1β, IL‐21, IL‐15 and tumour necrosis factor (TNF)‐α. In this study, the influence of a multifunctional cytokine, macrophage migration inhibitory factor (MIF), on IL‐17 production in mice was investigated. Treatment of lymph node cells (LNCs) with recombinant MIF up‐regulated mitogen‐stimulated IL‐17 expression and secretion. Additionally, LNCs from MIF knockout mice (mif−/−) had severely impaired production of IL‐17, as well as of IL‐1β, IL‐6, IL‐23 and TGF‐β. When stimulated with recombinant IL‐1β, IL‐23 or TNF‐α, mitogen‐triggered mif−/− LNCs were fully able to achieve the IL‐17 production seen in wild‐type (WT) LNCs, while the addition of IL‐6 and TGF‐β had no effect. Finally, after injection of mice with complete Freund’s adjuvant, secretion of IL‐17 as well as the number of IL‐17‐positive cells was significantly lower in the draining lymph nodes of mif−/− mice in comparison with WT mice. The effect of MIF on IL‐17 production was dependent on p38, extracellular signal‐regulated kinase (ERK), Jun N‐terminal kinase (JNK) and Janus kinase 2/signal transducer and activator of transcription 3 (Jak2/STAT3), and not on nuclear factor (NF)‐κB and nuclear factor of activated T cells (NFAT) signalling. Bearing in mind the contribution of MIF and IL‐17 to the pathology of inflammatory and autoimmune disorders, from the results presented here it seems plausible that targeting MIF biological activity could be a valid therapeutic approach for the treatment of such diseases.

Macrophage migration inhibitory factor deficiency leads to age-dependent impairment of glucose homeostasis in mice

“…IL6 and TNFa levels were not changed in older MIFK/K mice, whereas IL10 and MCP1 as well as leptin were increased. This observation is consistent with previous reports indicating that secretion of the proinflammatory cytokines IL6 and TNFa was unchanged or reduced in MIFK/K mice studied in a setting of inflammation (Amaral et al 2007, Stosic-Grujicic et al 2008, Stojanovic et al 2009). Moreover, Verschuren et al (2009) showed that genetic deletion of MIF in a mouse model of IR (the low-density lipoprotein receptor-deficient mouse) reduced macrophage infiltration in white adipose tissue, and lowered both tissue-specific and systemic chronic inflammation.…”

Increased activity of interleukin-23/interleukin-17 proinflammatory axis in obese women

“…20 Moreover, some recent studies indicate that leptin and MIF might also stimulate the expression of IL-17 in human and mouse mononuclear cells, respectively. 18,19 Our results, however, argue against the possibility that such a link might be operative in human obesity, as no correlation was observed between the levels of IL-17 or IL-23 and those of leptin or MIF in obese women. On the other hand, IL-17 showed a clear tendency toward positive correlation with IL-23 in obese subjects, which is consistent with the well-known role of IL-23 in inducing IL-17 secretion in T lymphocytes and other cell types.…”

“…Their exploration in obesity is warranted by recent findings indicating that the proinflammatory adipokine leptin and the proinflammatory cytokine macrophage migration inhibitory factor (MIF), both known to be increased in obese humans, 13-17 might stimulate IL-17 production in T cells. 18,19 The aim of this study was to investigate the activity of IL-23/IL-17 and IL-12/IFN-g cytokine axis in obesity, as well as their relationship with the proinflammatory mediators MIF and leptin. The association between cytokine levels and the major anthropometric and metabolic markers of obesity was also explored.…”

Identification of Iguratimod as an Inhibitor of Macrophage Migration Inhibitory Factor (MIF) with Steroid-sparing Potential

“…T-614 is known to suppress the IL-17 signaling axis, and MIF is known to stimulate this axis (85). T-614 has been shown to inhibit osteoclastic differentiation, which is induced by MIF (86,87).…”