Background and Aims Macrophage migration inhibitory factor (MIF) is a mediator of innate immunity and is implicated in the pathogenesis of numerous autoinflammatory disorders. Clinical studies have shown correlations between elevated levels of IL-1β and MIF in serum with disease outcomes of patients with autoimmune disorders. To date, it is unclear whether MIF specifically regulates the expression and secretion of IL-1 family cytokines. Therefore, we aim to characterise mechanisms by which MIF may modulate the secretion of IL-1 family cytokines.
Methods The biological activity of MIF in murine bone marrow derived macrophages (BMDM) was inhibited using a small molecule inhibitor, COR123625. Concurrently, BMDM derived from Mif-/- mice were employed to evaluate the effects of MIF depletion on regulation of IL-1 family cytokines. mRNA expression was analysed by qRTPCR. Protein expression and secretion of IL-1α, IL-1β and IL-18 was assessed by western blot and ELISA.
Results We show that depletion of MIF in macrophages significantly reduced IL-1 cytokine release specifically in response to NLRP3 stimuli, but has no effect on the secretion of TNF-α and IL-6. Moreover, diminished IL-1 responses were independent of production of pro-IL-1β. Instead, MIF depletion specifically inhibits NLRP3-mediated IL-1 responses as levels were unaffected following activation of AIM2 or NLRC4 inflammasomes.
Conclusions Our findings reveal a novel role for MIF in the modulation of IL-1-dependent inflammatory responses, linking MIF directly to NLRP3 inflammasome activation. This study for the first time implicates a specific role for MIF in the release of IL-1 family cytokines and highlights the potential of targeting MIF in IL-1-dependent pathologies.
- © 2017, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.