PT  - JOURNAL ARTICLE
AU  - Lang, T
AU  - Lee, J
AU  - Pinar, A
AU  - Fan, H
AU  - Mansell, A
AU  - Morand, E
AU  - Harris, J
TI  - 344 Linking macrophage migration inhibitory factor and nlrp3 in the pathogenesis of il-1 dependent inflammatory disorders
AID  - 10.1136/lupus-2017-000215.344
DP  - 2017 Mar 01
TA  - Lupus Science & Medicine
PG  - A151--A152
VI  - 4
IP  - Suppl 1
4099  - http://lupus.bmj.com/content/4/Suppl_1/A151.2.short
4100  - http://lupus.bmj.com/content/4/Suppl_1/A151.2.full
SO  - Lupus Sci & Med2017 Mar 01; 4
AB  - 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.