title: Macrophage migration inhibitory factor stimulates interleukin-17 expression and production in lymph node cells.
abstract: 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)-beta 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-1beta, IL-21, IL-15 and tumour necrosis factor (TNF)-alpha. 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-1beta, IL-6, IL-23 and TGF-beta. When stimulated with recombinant IL-1beta, IL-23 or TNF-alpha, 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-beta 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)-kappaB 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.
authors.affiliation: Department of Immunology, Institute for Biological Research Sinisa Stanković, University of Belgrade, Belgrade, Serbia. branicevo@yahoo.com
authors.forename: Ivana
authors.initials: I
authors.lastname: Stojanović
authors.forename: Tamara
authors.initials: T
authors.lastname: Cvjetićanin
authors.forename: Sandra
authors.initials: S
authors.lastname: Lazaroski
authors.forename: Stanislava
authors.initials: S
authors.lastname: Stosić-Grujicić
authors.forename: Djordje
authors.initials: D
authors.lastname: Miljković
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005620:Freund's Adjuvant; D007249:Inflammation / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000276:immunology; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; D005620:Freund's Adjuvant; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse