Macrophage migration inhibitory factor: a mediator of matrix metalloproteinase-2 production in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by destruction of bone and cartilage, which is mediated, in part, by synovial fibroblasts. Matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes responsible for matrix degradation. Macrophage migration inhibitory factor (MIF) is a cytokine that induces the production of a large number of proinflammatory molecules and has an important role in the pathogenesis of RA by promoting inflammation and angiogenesis.In the present study, we determined the role of MIF in RA synovial fibroblast MMP production and the underlying signaling mechanisms. We found that MIF induces RA synovial fibroblast MMP-2 expression in a time-dependent and concentrationdependent manner. To elucidate the role of MIF in MMP-2 production, we produced zymosan-induced arthritis (ZIA) in MIF gene-deficient and wild-type mice. We found that MMP-2 protein levels were significantly decreased in MIF gene-deficient compared with wild-type mice joint homogenates. The expression of MMP-2 in ZIA was evaluated by immunohistochemistry (IHC). IHC revealed that MMP-2 is highly expressed in wild-type compared with MIF gene-deficient mice ZIA joints. Interestingly, synovial lining cells, endothelial cells, and sublining nonlymphoid mononuclear cells expressed MMP-2 in the ZIA synovium. Consistent with these results, in methylated BSA (mBSA) antigen-induced arthritis (AIA), a model of RA, enhanced MMP-2 expression was also observed in wild-type compared with MIF gene-deficient mice joints. To elucidate the signaling mechanisms in MIF-induced MMP-2 upregulation, RA synovial fibroblasts were stimulated with MIF in the presence of signaling inhibitors. We found that MIF-induced RA synovial fibroblast MMP-2 upregulation required the protein kinase C (PKC), c-jun N-terminal kinase (JNK), and Src signaling pathways. We studied the expression of MMP-2 in the presence of PKC isoform-specific inhibitors and found that the PKCδ inhibitor rottlerin inhibits MIF-induced RA synovial fibroblast MMP-2 production. Consistent with these results, MIF induced phosphorylation of JNK, PKCδ, and c-jun. These results indicate a potential novel role for MIF in tissue destruction in RA. AIA = antigen-induced arthritis; BCA = bicinchoninic acid; CO 2 = carbon dioxide; COX2 = cyclo-oxygenase 2; DAPI = 4',6-diamidino-2-phenylindole dihydrochloride; DMSO = dimethyl sulfoxide; ECL = enhanced chemiluminescence; ED 50 = Median Effective Dose; ELISA = enzyme-linked immunosorbent assay; FBS = fetal bovine serum; IFN-γ; = interferon-γ; IHC = immunohistochemistry; IL-1β; = interleukin-1β; Jak = janus kinase; JNK = cjun N-terminal kinase; MAPK/ERK = mitogen-activated protein kinase extracellular-signal-regulated kinase; mBSA = methylated bovine serum albumin; MIF = macrophage migration inhibitory factor; MMP = matrix metalloproteinase; MT-MMP = membrane-type matrix metalloproteinase; NF-κB = nuclear factor-κB; OCT = optimal cutting temperature compound; PAGE = polyacrylamide gel electrophoresis; PB...

Activation of the JNK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on CXCR4 and CD74

“…MMP-2 induction by MIF in arthritic synovial fibroblasts was inhibitable, among other kinase pathway blockers, by a JNK I small molecule inhibitor [39]. MMP-9 and -13 induction in osteoblasts is also enhanced by activation of MIF and AP1, but MIF-mediated activation of c-Jun and c-Fos in these cells was independent of JNK and rather seemed to be due to an MIF/ERK1/2-dependent induction of c-Fos/c-Jun gene transcription [58].…”

“…The MIF/CD74 axis has not been shown to stimulate the JNK pathway, although MIF release inhibits signalling through JNK in ischemic cardiomyocytes [38]. MIF-induced MMP-2 production in rheumatoid synovial fibroblasts required activation of protein kinase C, JNK, and SRC signalling pathways [39]. On the other hand, Yu et al showed that MIF induces MMP-9 expression in murine macrophages mainly via the ERK1/2 MAPK pathway and only to a minor extent through JNK [40].…”

Clinical evaluation of the flotrac/vigileo™ system for continuous cardiac output monitoring in patients undergoing regional anesthesia for elective cesarean section: a pilot study

“…MIF is an important cytokine that regulates both adaptive and immune responses 3. It is a potent pro-inflammatory cytokine that has been reported to stimulate TNF and IL-6 expression4 and an important downstream marker of inflammation. C-reactive protein (CRP) is one of the acute phase proteins that increase during systemic inflammation 5,6.…”

Macrophages and angiogenesis in rheumatic diseases

“…Remodeling of the extracellular matrix by MMPs is important in angiogenesis. Among the various subtypes of MMPs, MMP-1, MMP-2 and MMP-9 expression levels have been demonstrated in rheumatoid synovial macrophages [20,21]. Moreover, synovial macrophages also express tissue inhibitors of MMPs (TIMPs) that contrast the effects of MMPs [20].…”

“…Moreover, macrophage migration-inhibitory factor (MIF) is expressed by macrophages in the synovium, where it is responsible for inducing macrophage production of angiogenic agents, including TNF-α, IL-1, IL-6, IL-8/CXCL8 and MMPs production [21,39]. In animal models of rheumatoid arthritis, MIF antagonism or deficiency result in decreased disease severity [58].…”