Macrophage migration inhibitory factor has a proinflammatory activity via the p38 pathway in glucocorticoid-resistant ulcerative colitis☆
Introduction
Ulcerative colitis (UC) is a chronic, relapsing, inflammatory bowel disease (IBD). About 15% of cases require intravenous steroid administration because of the severity of the attack. As the response rate is about 60% [1], it is of interest to determine the pathogenesis of glucocorticoids (GC) refractoriness, which may also help to predict the prognostic outcome and avoid overuse of GC. Although the etiology of IBD is still unknown, immunological factors, including overproduction of proinflammatory cytokines, are highly likely to have an important role in its pathogenesis. Proinflammatory cytokines are abundant in intractable cases of UC regardless of steroid therapy rather than responsive and other inflammatory controls [2], and the ability of immunosuppressive drugs and recent biological agents that were shown to ameliorate the disease [3], [4] supports this hypothesis. Several factors are known to play a role in steroid refractoriness, such as antagonistic glucocorticoid receptor β [5] and P-glycoprotein-1 [6], and other factors may also be involved. Macrophage migration inhibitory protein (MIF) is a cytokine that was first described for its inhibitory effect on the migration of macrophages. Recent in vivo and in vitro studies [7], [8], [9], [10], [11] have established the activity of MIF as a proinflammatory cytokine.
One of the significant roles of MIF is to overcome the anti-inflammatory effect of GC on proinflammatory cytokine production stimulated by lipopolysaccharide (LPS) [12]. It was also shown that MIF induces matrix metalloproteinase in rheumatoid arthritis synovium via AP-1 [13], and the mortality rate was improved by anti-MIF antibody in a septic shock model [7].
Although MIF has been implicated in pathogenesis in a colitis model [14], and serum levels of MIF in IBD patients are increased [15], more studies are needed to elucidate the role of MIF in UC. In the present study, MIF was significantly higher in refractory cases, and the overcoming effect of MIF on GC treatment was described. Anti-MIF Ab ameliorated GC-resistant IL-8 production and p38-MAPK activity in refractory cases. Furthermore, SB203580 ameliorated IL-8 production in the refractory cases. These results suggest that MIF has additional proinflammatory activities through the p38 pathway in refractory cases with UC.
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Patient population
Because there are several clinical variations of refractory UC including unresponsive fluminant disease, unresponsive chronic disease, and steroid-dependent disease, several criteria have been reported previously [6], [16], [17]. We defined refractory UC as no response to at least 2 weeks of prior intravenous GC therapy, and as a result, all refractory patients who were assessed in this study were surgically treated. Eight cases of refractory UC (5 male and 3 female; age range 16–56 years, mean
MIF was strongly induced in refractory cases with UC
MIF transcripts were strongly induced in refractory cases with UC (0.368 ± 0.053) rather than responder (0.219 ± 0.023, P < 0.05), controls (0.127 ± 0.021, P < 0.01) and CD (0.1465 ± 0.053, P < 0.05). MIF transcripts in the responder were also higher than in the controls and CD (P < 0.05, P < 0.05).
Immunohistochemical study revealed that MIF-positive cells were compatible with LPMC in all groups (Fig. 2) and increased in refractory cases with UC (Figs. 2B, C) rather than in the controls (Fig. 2
Discussion
The mechanism of GC refractoriness of UC is still unclear. Large amounts of proinflammatory cytokines such as IL-1β, IL-8, IL-6 and TNF-α in the chronic phase in spite of GC therapy might be involved [2], [22], and many of the transcriptional factors regulate these inflammatory networks. GC has been shown to inhibit the signaling in these pathways [23], [24], [25], whereas the RelA p65 subunit of NF-κB [26], p38-MAPK [26] and AP-1 [27], [28] antagonize the effect of GC. MIF is also thought to
Acknowledgment
This work was supported in part by the Research Committee of Inflammatory Bowel Disease provided by the Japanese Ministry of Health, Labor, and Welfare.
References (32)
- et al.
The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study
Gastroenterology
(2001) - et al.
Intravenous cyclosporin in ulcerative colitis: a five-year experience
Am. J. Gastroenterol.
(1999) - et al.
Expression of glucocorticoid receptor beta in lymphocytes of patients with glucocorticoid-resistant ulcerative colitis
Gastroenterology
(2000) - et al.
Macrophage migration inhibitory factor up-regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis
J. Biol. Chem.
(2000) - et al.
Amelioration of dextran sulfate sodium-induced colitis by anti-macrophage migration inhibitory factor antibody in mice
Gastroenterology
(2002) - et al.
Ultraviolet A-induced production of matrix metalloproteinase-1 is mediated by macrophage migration inhibitory factor (MIF) in human dermal fibroblasts
J. Biol. Chem.
(2004) Inflammatory bowel disease: etiology and pathogenesis
Gastroenterology
(1998)- et al.
Functional antagonism between oncoprotein c-Jun and the glucocorticoid receptor
Cell
(1990) - et al.
Transcriptional interference between c-Jun and the glucocorticoid receptor: mutual inhibition of DNA binding due to direct protein-protein interaction
Cell
(1990) Mucosal proinflammatory cytokine production correlates with endoscopic activity of ulcerative colitis
J. Gastroenterol.
(1999)
Azathioprine or methotrexate in the treatment of patients with steroid-dependent or steroid-resistant ulcerative colitis: results of an open-label study on efficacy and tolerability in inducing and maintaining remission
Aliment. Pharmacol. Ther.
High multidrug resistance (P-glycoprotein 170) expression in inflammatory bowel disease patients who fail medical therapy
Gastroenterology
Regulatory role for macrophage migration inhibitory factor in acute respiratory distress syndrome
Nat. Med.
MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia
Nature
Purification, bioactivity, and secondary structure analysis of mouse and human macrophage migration inhibitory factor (MIF)
Biochemistry
Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1
Nature
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This work was performed at Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.