Elsevier

Clinical Immunology

Volume 120, Issue 3, September 2006, Pages 335-341
Clinical Immunology

Macrophage migration inhibitory factor has a proinflammatory activity via the p38 pathway in glucocorticoid-resistant ulcerative colitis

https://doi.org/10.1016/j.clim.2006.05.010Get rights and content

Abstract

Macrophage migration inhibitory factor (MIF) is a cytokine that has potent anti-steroid effects and might be implicated in the pathogenesis of Ulecrative colitis (UC). We defined the functional role of MIF in the glucocorticoid (GC)-resistant inflammatory response in UC. Twenty-four colonic samples were obtained from GC responsive cases, GC refractory cases, Crohn's disease and controls. LPMC were isolated from surgical specimens. MIF was strongly expressed at mRNA levels in refractory cases rather than responsive cases with UC and controls. IL-8 production from LPMC was significantly reduced by GC addition in responsive cases but not in refractory cases. In refractory cases, anti-MIF Ab ameliorated GC-resistant IL-8 production and p38-MAPK activity of LPMC. In addition, p38-MAPK antagonist SB230580 also ameliorated GC-resistant IL-8 production. These results suggest that MIF has an additional proinflammatory activity through the p38-MAPK pathway in GC-resistant UC.

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.

Section snippets

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)

  • O.A. Paoluzi et al.

    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.

    (2002)
  • R.J. Arrell et al.

    High multidrug resistance (P-glycoprotein 170) expression in inflammatory bowel disease patients who fail medical therapy

    Gastroenterology

    (2000)
  • S.C. Donnelly et al.

    Regulatory role for macrophage migration inhibitory factor in acute respiratory distress syndrome

    Nat. Med.

    (1997)
  • J. Bernhagen et al.

    MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia

    Nature

    (1993)
  • J. Bernhagen et al.

    Purification, bioactivity, and secondary structure analysis of mouse and human macrophage migration inhibitory factor (MIF)

    Biochemistry

    (1994)
  • R. Kleemann et al.

    Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1

    Nature

    (2000)
  • Cited by (56)

    • Regulating effect of baicalin on IKK/IKB/NF-kB signaling pathway and apoptosis-related proteins in rats with ulcerative colitis

      2019, International Immunopharmacology
      Citation Excerpt :

      The aminosalicylic acid is still the mainstay of UC treatment. Glucocorticoid has strong anti-inflammatory effect and rapid induction, but considering its adverse reactions and hormone dependence or resistance, clinical application should strictly control its indications and methods of use [12,13]. Baicalin, a flavonoid compound purified from the dry roots of Scutellaria baicalensis Georgi, has generally been used for the treatment of various allergic diseases [14].

    View all citing articles on Scopus

    This work was performed at Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.

    View full text