Elsevier

Cytokine

Volume 26, Issue 5, 7 June 2004, Pages 187-194
Cytokine

Inhibition of joint inflammation and destruction induced by anti-type II collagen antibody/lipopolysaccharide (LPS)-induced arthritis in mice due to deletion of macrophage migration inhibitory factor (MIF)

https://doi.org/10.1016/j.cyto.2004.02.007Get rights and content

Abstract

Objective

Previous studies have demonstrated that neutralization of macrophage migration inhibitory factor (MIF) by anti-MIF antibody decreases joint destruction in the collagen-induced arthritis model. The present study was undertaken to investigate whether selective deletion of MIF inhibits inflammation and joint destruction of the anti-type II collagen antibody (anti-CII Ab)/lipopolysaccharide (LPS)-induced arthritis in mice, in order to determine the role of this cytokine in inflammatory arthritis.

Design

Anti-CII Ab/LPS-induced arthritis was induced in MIF-deficient and wild-type mice. The effects of anti-MIF polyclonal antibody administration on anti-CII Ab-induced arthritis were also evaluated.

Results

The expression of MIF protein and mRNA was induced in anti-CII Ab/LPS-induced arthritis joint tissues. Histopathological arthritis scores for synovial inflammation induced by anti-CII Ab/LPS -induced arthritis were significantly decreased in anti-MIF Ab-treated mice and in MIF-deficient mice compared to wild-type mice. In addition, mRNA levels of MMP-13 and MIP-2 in anti-CII Ab/LPS-induced arthritis joint tissues were significantly reduced in MIF-deficient mice compared to wild-type control mice.

Conclusions

These results indicate that MIF plays a critical role in inflammation and joint destruction in the anti-CII Ab/LPS-induced arthritis model in mice, in part via induction of MMP-13 and neutrophil infiltration through the induction of MIP-2.

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease characterized by accelerated proliferation of synovial cells, which eventually leads to the destruction of cartilage and bone in the joint [1]. Synovial cells play a major role in the pathogenesis of RA through the synthesis of various cytokines and proteases.

Macrophage migration inhibitory factor (MIF) was initially identified as a soluble factor in the culture medium of activated T cells [6], [7]; however, its precise biological function has long remained unclear. Following the cloning of MIF cDNA [8], previously unrecognized biological functions of MIF have been revealed. MIF is released as a hormone by the anterior pituitary gland in endotoxin shock [9], [10], and as a proinflammatory cytokine and glucocorticoid-induced immunomodulator primarily produced by macrophages in response to a variety of inflammatory stimuli [11].

MIF is also an important factor in the pathomechanism of RA. We have already reported that MIF, which has recently been re-evaluated as a mediator in various inflammatory diseases, is exclusively expressed in CD45(+) T cells of rheumatoid synovium, and that the concentrations of MIF in the joint fluids are much higher in RA patients than in osteoarthritis (OA) patients or normal volunteers [12]. MIF induces the production of TNF-α by macrophages [11], [13]. MIF also stimulates nitric oxide production by macrophages primed with interferon-gamma [13]. MIF upregulates MMP and COX-2 mRNA in rheumatoid synovial fibroblasts [14], [15]. Monoclonal antibodies to MIF have been shown to have profound inhibitory effects on joint inflammation in rodent animal models of RA [16], [17]. Both the synovial expression of MIF and the promoter polymorphism in the MIF gene have been reported to be correlated with disease activity in RA [18], [19]. These data make it clear that MIF is an important cytokine in the pathomechanism of RA. However, the role of MIF in RA still remains unclear.

In rat and mouse, MIP-2 is one of the major neutrophil chemoattractant factors [2], [3]. MIP-2 levels have been reported to be elevated in an experimental arthritis model [4]. Also, neutralization of MIP-2 has been found to significantly decrease the severity of CIA [5]. These findings illustrate the importance of MIP-2 in the murine experimental arthritis model.

In the present study, we injected a mixture of mAbs raised against type II collagen to induce rheumatoid arthritis in wild-type and MIF-deficient mice and examined the role of MIF in the process of arthritis. We found that MIF-deficiency significantly suppresses joint inflammation and mRNA upregulation of MMP-13 and MIP-2. The present results should provide further insight into the regulatory mechanism of inflammation in joint arthritis.

Section snippets

Animals

In the present study, we used MIF-deficient mutant mice with generation numbers of F11 to F13 from a mouse strain (bred onto a BALB/c background) deficient in the MIF gene, which was established by Honma et al. [20]. Briefly, they generated a gene targeting vector containing the endogenous MIF gene in which a 201-bp SacI fragment consisting of the 3′ region of exon 1 and the 5′ region of intron 1 was replaced with a pMCI-neo poly (A) cassette in a forward orientation relative to MIF gene

Expression of MIF protein in synovium was enhanced in arthritis-induced mice

The swelling of joints in wild-type mice injected with mAb/LPS began to rise on day 4, and peaked by day 7. The photograph shows the hindpaw of mouse injected with mAb/LPS on day 14 (Fig. 1a). Histological examination indicated that inflammatory cells infiltrated into the synovial tissue in wild-type mice injected with mAbs/LPS (Fig. 1b). We observed MIF protein expression in the ankle joints by MIF immunostaining. In wild-type mice, the number of MIF-positive cells in synovia was apparently

Discussion

In the passive-transfer arthritis model, the administration of LPS following administration of mAbs against type II collagen is essential for arthritis to occur. Concerning this, Terato et al. [22] have assumed that (1) LPS enhances the deposition of antibodies onto the cartilage surface, which is supported by the observation of a remarkable enlargement of chondrocytes at the cartilage surface layer following LPS administration; and that (2) LPS induces the release of PMN-chemotactic cytokines

Acknowledgments

We are grateful to Mutsuko Funatsu B. S. of the Department of Sports Medicine and Joint Reconstruction Surgery for his technical assistance.

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