SUMMARY(MIF) is a broad-spectrum proinflammatory cytokine implicated in human rheumatoid arthritis. The synthesis of MIF by synovial cells is stimulated by glucocorticoids, and previous studies suggest that MIF antagonizes the anti-inflammatory effects of glucocorticoids. This has not been established in a model of arthritis. We wished to test the hypothesis that MIF can act to reverse the anti-inflammatory effects of glucocorticoids in murine antigen-induced arthritis (AIA). Cutaneous DTH reactions and AIA were induced by intradermal injection and intra-articular injection, respectively, of methylated bovine serum albumin in presensitized mice. Animals were treated with anti-MIF MoAbs, recombinant MIF, and/or dexamethasone (DEX). Skin thickness of DTH reactions was measured with callipers and arthritis severity was measured by blinded quantitative histological assessment of synovial cellularity. Cutaneous DTH to the disease-initiating antigen was significantly inhibited by anti-MIF MoAb treatment (P , 0´001). AIA was also significantly inhibited by anti-MIF MoAb (P , 0´02). DEX treatment induced a dose-dependent inhibition of AIA, which was significant at 0´2 mg/kg (P , 0´05). MIF treatment reversed the effect of therapeutic DEX on AIA (P , 0´001). DEX also significantly inhibited DTH reactions (P , 0´05) but rMIF had no effect on this effect of DEX. DTH and AIA are MIFdependent models of inflammation and arthritis. The reversal of glucocorticoid suppression of AIA by MIF supports the concept that MIF is a counter-regulator of glucocorticoid control of synovial inflammation. Although DTH was observed to be MIF-dependent and glucocorticoid-sensitive, rMIF had no reversing effect on the suppression of DTH by glucocorticoids. This suggests that inflammatory processes in specific tissues may respond differently to MIF in the presence of glucocorticoids.
Objective. Glucocorticoid-induced leucine zipper (GILZ) is a glucocorticoid-induced protein, the reported molecular interactions of which suggest that it functions to inhibit inflammation. However, the role of endogenous GILZ in the regulation of inflammation in vivo has not been established. This study was undertaken to examine the expression and function of GILZ in vivo in collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis (RA), and in RA synoviocytes.Methods. GILZ expression was detected in mouse and human synovium by immunohistochemistry and in cultured cells by real-time polymerase chain reaction and permeabilization flow cytometry. GILZ function was assessed in vivo by small interfering RNA (siRNA) silencing using cationic liposome-encapsulated GILZ or control nontargeting siRNA and was assessed in vitro using transient overexpression.Results. GILZ was readily detectable in the synovium of mice with CIA and was up-regulated by therapeutic doses of glucocorticoids. Depleting GILZ expression in vivo increased the clinical and histologic severity of CIA and increased synovial expression of tumor necrosis factor and interleukin-1 (IL-1), without affecting the levels of circulating cytokines or anticollagen antibodies. GILZ was highly expressed in the synovium of patients with active RA and in cultured RA synovial fibroblasts, and GILZ overexpression in synovial fibroblasts inhibited IL-6 and IL-8 release.Conclusion. Our findings indicate that GILZ functions as an endogenous inhibitor of chronic inflammation via effects on cytokine expression and suggest that local modulation of GILZ expression could be a beneficial therapeutic strategy.Chronic inflammation in rheumatoid arthritis (RA) is mediated by complex interactions of macrophages, T cells, and resident cells through the effects of multiple proinflammatory cytokines. Proinflammatory events are balanced by antiinflammatory regulatory pathways, one of the most important of which is mediated by endogenous glucocorticoids. During inflammation, circulating cytokines stimulate the hypothalamicpituitary-adrenal axis, resulting in the release of endogenous glucocorticoids and subsequent inhibition
Macrophage migration inhibitory factor (MIF) promotes leukocyte recruitment to sites of inflammation. However, whether this stems from a direct effect on leukocyte migration is unknown. Furthermore, the role of the MIF-binding protein CD74 in this response has not been investigated. Therefore the aim of this study was to examine the contributions of MIF and CD74 to chemokine-induced macrophage recruitment. Intravital microscopy studies demonstrated that CCL2-induced leukocyte adhesion and transmigration were reduced in MIF−/− and CD74−/− mice. MIF−/− and CD74−/− macrophages also exhibited reduced chemotaxis in vitro, although CD74−/− macrophages showed increased chemokinesis. Reduced CCL2-induced migration was associated with attenuated MAPK phosphorylation, RhoA GTPase activity and actin polymerization in MIF−/− and CD74−/− macrophages. Furthermore, in MIF−/− macrophages, MAPK phosphatase-1 (MKP-1) was expressed at elevated levels, providing a potential mechanism for the reduction in MAPK phosphorylation in MIF-deficient cells. No increase in MKP1 expression was observed in CD74−/− macrophages. In in vivo experiments assessing the link between MIF and CD74, combined administration of MIF and CCL2 increased leukocyte adhesion in both MIF−/− and CD74−/− mice, showing that CD74 was not required for this MIF-induced response. In addition, although leukocyte recruitment induced by administration of MIF alone was reduced in CD74−/− mice, consistent with a role for CD74 in leukocyte recruitment induced by MIF, MIF-treated CD74−/− mice displayed residual leukocyte recruitment. These data demonstrate that MIF and CD74 play previously unappreciated roles in chemokine-induced macrophage adhesion and migration, and indicate that MIF and CD74 mediate this effect via both common and independent mechanisms.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.