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)
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.
References (32)
- et al.
High expression of macrophage migration inhibitory factor in the synovial tissues of rheumatoid joints
Cytokine
(1999) - et al.
Macrophage migration inhibitory factor (MIF) up-regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis
J Biol Chem
(2000) - et al.
Macrophage migration inhibitory factor is an important mediator in the pathogenesis of gastric inflammation in rats
Gastroenterology
(2001) - et al.
Arthritis Rheum
(2001) - et al.
Properties of the novel proinflammatory supergene “intercrine” cytokine family
Annu Rev Immunol
(1991) - et al.
Interleukin-8 and related chemotactic cytokines—CXC and CC chemokines
Adv Immunol
(1994) - et al.
The importance of IL-1β and TNF-α, and the noninvolvement of IL-6, in the development of monoclonal antibody-induced arthritis
J Immunol
(2002) - et al.
Interleukin-10 expression and chemokine regulation during the evolution of murine type-II collagen-induced arthritis
J Clin Invest
(1995) - et al.
Mechanism of a reaction in vitro associated with delayed-type hypersensitivity
Science
(1966) Delayed hypersensitivity in vitro: its mediation by cell free substances formed by lymphoid cell–antigen interaction
Proc Natl Acad Sci U S A
(1966)