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Rheumatology Advance Access originally published online on May 16, 2006
Rheumatology 2006 45(8):937-943; doi:10.1093/rheumatology/kel142
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

REVIEW

Macrophage migration inhibitory factor and glucocorticoid sensitivity

D. Aeberli, M. Leech and E. F. Morand

Centre for Inflammatory Diseases, Monash Institute for Medical Research, Monash Medical Centre, Clayton, Melbourne, Australia.

Correspondence to: Eric Morand, Centre for Inflammatory Diseases, Monash Medical Centre, Locked Bag No 29, Clayton Melbourne 3168, Australia. E-mail: eric.morand{at}med.monash.edu.au


   Abstract
Top
 Abstract
Introduction
 Macrophage migration inhibitory...
 The role of MIF...
 MIF and GCs
 Potential toxicity of MIF...
 Conclusions
 References
 
Glucocorticoids (GCs) are widely used in the treatment of inflammatory diseases including rheumatoid arthritis (RA). Treatment with GC is associated with significant dose-dependent side-effects. The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) has emerged in recent years as a candidate factor which could regulate GC sensitivity. MIF is induced by GC, and is able to override anti-inflammatory actions of GCs. In this review, we summarize the pro-inflammatory actions of MIF with respect to RA, describe the interactions between MIF and GC and examine new evidence, which identifies MIF as a specific target for steroid sparing.

KEY WORDS: MIF, Glucocorticoids, Steroid sparing, Rheumatoid arthritis


   Introduction
Top
 Abstract
 Introduction
Macrophage migration inhibitory...
 The role of MIF...
 MIF and GCs
 Potential toxicity of MIF...
 Conclusions
 References
 
Glucocorticoids (GCs) represent the most important and frequently used class of anti-inflammatory drugs in routine clinical practice [1]. Since the successful use of cortisol (the principal GC of the adrenal cortex) in 1948, GCs have become so important that some authors divide the history of rheumatology into ‘BC and AC’ (i.e. before and after cortisol) [2]. The utility of GC relates largely to their capacity to reduce the recruitment of inflammatory cells and suppress the pro-inflammatory cytokine and mediator synthesis, thereby effectively blocking the inflammatory cascade at many levels [3]. From the community survey data, the prevalence of oral GC use has been estimated to be 0.5% of the general population and 1.4% of those older than 55 yrs [4, 5]. In the US, the cost of GC use is estimated as 10 billion US dollars per year [1].

Despite the use of new biological disease modifying drugs in rheumatoid arthritis (RA), between 56 and 68% of patients continue to require GC therapy [6, 7]. The duration, dosage and dose regimens of GC for RA are numerous, ranging from low dose (<7.5 mg/day) to the so-called pulse therapy with up to 1.5 g methylprednisolone per day [8]. Although GCs are clearly beneficial [9], substantial dose-dependent and often irreversible side-effects are recognized, which limit their use [10]. Side-effects of most concern include hypertension, obesity, osteoporosis, myopathy, oedema and immune compromise. Premature death related to atherosclerosis is also increasingly recognized in inflammatory diseases including RA and systemic lupus erythematosus [11–15], and the potential contribution of GC therapy to atherosclerosis in this setting is suggested by a number of studies [16]. A recent study in RA patients found that GC exposure was associated with increased carotid plaque incidence [17].

The substantial burden of toxicity of GC mandates the development of specific ‘steroid-sparing’ therapies, which would facilitate the action of GC on inflammatory disease and allow dose reduction. This requires the elucidation of factors that regulate GC sensitivity. In recent years, a unique relationship between the cytokine macrophage migration inhibitory factors (MIFs) and GCs has been emerged, identifying MIF as a candidate factor that could regulate GC sensitivity. This article will review the pro-inflammatory actions of MIF with specific reference to RA, and will examine new evidence that identifies it as an endogenous regulator of GC sensitivity, and hence as a specific target for steroid sparing.


   Macrophage migration inhibitory factor (MIF)
Top
 Abstract
 Introduction
 Macrophage migration inhibitory...
The role of MIF...
 MIF and GCs
 Potential toxicity of MIF...
 Conclusions
 References
 
The existence of leucocyte and MIFs has been hypothesized since the experiments of Rich and Lewis [18], in which tuberculin-induced delayed-type hypersensitivity (DTH) reactions were associated with the inhibition of macrophage migration. About 30 yrs later, Bloom and Bennett [19] and David [20] found that migration inhibition in the DTH model was caused by a soluble T-cell derived factor, and the name MIF was coined. In 1993, Bernhagen et al. [21] succeeded in producing a recombinant MIF, which led to the discovery of the structure and functions of MIF over the last decade.

MIF is 12.5 kDa protein that is highly conserved, with mouse and rat MIF exhibiting 90% homology over 114 amino acids with human MIF [22]. The X-ray crystal structure of MIF has been reported to 2.6 Å resolution and is a trimer of three identical monomers. Each monomer consists of two anti-parallel {alpha} helices and six ß strands of which four build a ß-sheet [23]. The trimeric structure of MIF possesses an enzymatic function, catalysing the tautomerization of D-dopachrome [24], but the relevance of this reaction to the biology of MIF remains obscure.

MIF is expressed in a wide variety of cell types including lymphocytes, monocytes and macrophages, endothelial cells and fibroblasts [25]. Furthermore, MIF is an important component of the neuro-endocrine system [21, 26, 27], and has been detected in neurons of the cortex, hypothalamus, hippocampus, cerebellum, pons as well as in the peripheral nerves [27, 28]. MIF is also expressed in reproductive tissues such as ovarian and testis [29, 30], human kidneys, especially in renal tubular epithelial cells, as well as in human keratinocytes and ocular lens cells [31–33].

MIF–/– mice were first generated in 1999 by disruption and deletion of exon 3 in the MIF gene [34]. MIF–/– mice were since then shown to be less susceptible to collagen antibody- and antigen-induced arthritis [35, 36], sepsis and toxic-shock syndrome [34, 37], atherogenesis [38], colitis [39], asthma [40], encephalomyelitis [41] and ovariectomy-induced bone loss [42]. On the other hand, MIF transgenic mice, carrying a murine MIF cDNA driven by a cytomegalovirus enhancer, were shown to be markedly more susceptible to the experimental colitis [43] and renal podocyte injury with progressive mesangial sclerosis in the kidney [44]. In contrast to the effects on inflammation, MIF–/– mice have normal growth, fertility and development.

A specific cell surface binding site for MIF was reported in 2003 [45]. MIF binds to the extracellular domain of a type II transmembrane protein, CD74. CD74–/– cells were non-responsive to MIF in vitro and soluble CD74 inhibited MIF-mediated cell signalling [45]. The major intracellular signalling events entrained by MIF are activation of the mitogen-activated protein kinase (MAPK) pathways. Many cytokines operative in RA act through both the nuclear factor-{kappa}B (NF-{kappa}B) and MAPK pathways [46]. In contrast, MIF appears to act selectively via the MAPKs extracellular signal-regulated kinases (ERK)1/2 and p38 [47–49]. To date, consistent evidence for direct activation of the NF-{kappa}B pathway by MIF is lacking [49, 50]; for example Lacey et al. [51] found no effect of MIF on translocation of the p50 and p65 subunits of NF-{kappa}B in RA fibroblast-like synoviocytes (FLS). As we shall discuss, this selective utilization of MAPK pathways may be highly relevant to a newly described mechanism of interaction between MIF and GC.


   The role of MIF in RA
Top
 Abstract
 Introduction
 Macrophage migration inhibitory...
 The role of MIF...
MIF and GCs
 Potential toxicity of MIF...
 Conclusions
 References
 
Considerable evidence supports the potential role of MIF in the pathology of RA. MIF is expressed in human RA synovial tissue macrophages, FLS and T-lymphocytes, and is over expressed in serum, synovial fluid and cultured FLS from RA patients compared with controls [52]. Furthermore, synovial MIF expression correlates with RA disease activity, as measured by serum C-reactive protein [53]. The potential role of MIF in the pathogenesis of RA is supported by its involvement in a range of experimental arthritis models, wherein antagonism or deletion of MIF affords suppression of disease [35, 36, 54–56]. Furthermore, the discovery of a polymorphism in the gene for human MIF that is significantly associated with increased MIF expression and with juvenile RA supports the involvement of MIF in the pathogenesis of RA [57, 58]. Most recently, a correlation between this polymorphism, serum MIF levels and radiological joint damage in patients with RA was reported [59]; if confirmed this would suggest MIF as a readily measurable serum predictor of outcome for RA.

The mechanisms of action of MIF in RA have more recently been explored. MIF expression is detected in synovial microvascular endothelial cells [52], which is consistent with its role in endothelial cell activation and angiogenesis [60–62]. MIF is now known to be required for normal leucocyte–endothelial interactions in vivo including in the inflamed joint [63]: in these studies, the MIF-deficient mice exhibited reduced leucocyte recruitment to the inflamed joint compared with the MIF-expressing mice. Many cytokines important in the synovial lesion of RA are also known to be regulated by MIF, including TNF, IL-1, IL-6, IL-8 and IFN{gamma} [64–66] (Table 1). There is also evidence that MIF up-regulates the expression of prostaglandin E2 via regulation of the expression of phospholipase A2 and cyclooxygenase 2 [67]. MIF also regulates the expression of matrix metalloproteinases (MMP)-9 and MMP-13 [68], which suggests potential involvement of MIF in cartilage destruction. In addition to induction of gene expression, it has been shown that MIF can stimulate synovial RA FLS proliferation in vitro [51]. Moreover, MIF inhibits the expression of the endogenous tumour suppressor protein p53 [69], including in synovial fibroblasts, and directly inhibits synoviocyte apoptosis [70]. Inactivation of p53 has previously been shown to increase FLS invasiveness into cartilage extracts [71], and MIF has been shown to regulate synovial p53 expression and apoptosis in vivo [70].


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  		TABLE 1. Reciprocal effects of MIF and GC on the pathology of RA

 
Similarly to TNF and IL-1, therefore, MIF is a key pro-inflammatory cytokine in RA. MIF is distinct from these cytokines, however, in its complex relationship with GC, through which MIF may modulate sensitivity to both endogenous and therapeutic GC.


   MIF and GCs
Top
 Abstract
 Introduction
 Macrophage migration inhibitory...
 The role of MIF...
 MIF and GCs
Potential toxicity of MIF...
 Conclusions
 References
 
Reciprocal regulation of inflammation by MIF and GCs
Unlike other pro-inflammatory cytokines, which are uniformly suppressed by GC, MIF expression can be induced by GC. This induction is biphasic and concentration dependent, occurring maximally at low physiological concentrations such as 10–11–10–9M dexamethasone [52, 64, 66]. This observation has been made in a variety of cells, including T-cells and macrophages as well as RA synovial fibroblasts [52]. Despite being induced by GC, MIF is able to directly antagonize their effects. This has been shown to be the case for the secretion of TNF, IL-1, IL-6, IL-8 and IFN{gamma} [64–66], and for T-cell proliferation and IL-2 release [66]. MIF also exhibits GC-antagonistic effects in vivo, in models involving both innate and adaptive immune responses such as endotoxic shock and antigen-induced arthritis [54, 64]. In endotoxic shock, for example, exogenous MIF overrides GC inhibition of lethality [64]. In murine antigen-induced arthritis, GC inhibition of histological severity of disease is reversed by exogenous MIF [54]. In keeping with this, Leech et al. [72] showed, in rat adjuvant arthritis, that increased joint inflammation and lethality in the absence of GC can be overridden by the neutralization of MIF. These data suggest a reciprocal relationship between MIF and GC in the control of the inflammatory response.

Studies in human subjects support the contention that MIF and GC operate reciprocally in the regulation of inflammatory response. A recent study by Berdeli et al. [73] reported an association between the MIF polymorphism noted above and GC resistance in children with nephrotic syndrome. This polymorphism has also been associated with reduced clinical response to GC in juvenile RA [74].

These data suggest that MIF functions as a physiological counter-regulator of the anti-inflammatory effects of GC. The value of this to the organism may relate to the need for the immune response to develop in the context of GC exposure. GCs are of course required for physiological regulation of many genes, and GC deprivation is a highly pathological state, but as a vigorous immune response to pathogens is also required for health, it is necessary for the immune system to function despite omnipresent GC. MIF may act so that the immune system retains normal function even during times of high physiological GC exposure, such as during stress. This effect of MIF means, however, that pharmacological GC may not exert optimal effects because of the induction of MIF. If this is correct, then MIF antagonism could provide a direct and specific route to ‘steroid-sparing’.

Regulation of GC sensitivity by MIF
Support for a potential steroid-sparing effect of MIF antagonism has very recently been elucidated. Two laboratories have independently reported that deficiency of MIF, either through genetic deletion in MIF–/– mice or by the use of anti-sense oligonucleotide, results in a left-shift in the dose-response to GC of the macrophage TNF production [75, 76]; in other words, the presence of MIF reduces GC sensitivity and its absence increases GC sensitivity. A shift in GC sensitivity in the absence of MIF of at least 3-fold was described, a difference that would clearly be clinically highly desirable. These represent the first demonstrations that MIF does indeed directly regulate GC sensitivity.

The molecular pathways involved in the regulation of GC-sensitivity by MIF have now been elucidated. The anti-inflammatory effects of GC are mediated by glucocorticoid receptors (GR). Biological effects mediated via the cytosolic GR (cGR) are mediated either by transrepression or transactivation of the target genes. Evidence exists for potential interactions of MIF with both transrepression and transactivation entrained by GC, but recent data strongly suggests a dominant effect of MIF on a single transactivation pathway involved in the regulation of GC sensitivity.

Inhibitory effects of MIF on GC-induced transactivation of MKP-1
Transactivation of gene expression is mediated by binding of the occupied GR to a GC response element (GRE) on a gene's promoter region. Transactivation is DNA-dependent, and in addition to inducing anti-inflammatory genes is also assumed to be an important mechanism of GC side effects including osteoporosis and glucose intolerance [1].

A recently described target of GC transactivation is the MAP kinase phosphatase (MKP)-1 [77]. MKP-1 belongs to a family of 11 members, which inactivate MAPKs via dephosphorylation of their regulatory serine/threonine and tyrosine residues [78]. MKP-1, the archetypal MKP, is constitutively expressed but is also strongly GC inducible [77]. GCs transcriptionally induce MKP-1 gene expression and inhibits MKP-1 protein degradation via attenuation of the proteasome pathway [78]. In RA FLS, Toh et al. [79] showed that GCs rapidly and sustainably up-regulate MKP-1 expression, and this effect was associated with the reciprocal down-regulation of MAPK activation. The inhibition of MAPK activity in this manner leads to inhibition of downstream events such as AP-1 activation, thus reducing AP-1 induction of many key pro-inflammatory genes [80]. MKP-1 has recently been shown to be a critical endogenous anti-inflammatory regulator of collagen-induced arthritis (CIA) and innate immune responses transduced by the toll-like receptors (TLRs) [81, 82]. Studies on the interaction of MIF with MKP-1 by the authors [75] and Roger et al. [76] have provided first insight into the mechanism through which MIF overrides GC action. Aeberli et al. [75] showed counter-regulation of GC-induced MKP-1 expression by endogenous and recombinant MIF (rMIF) in MIF–/– peritoneal macrophages, resulting in a sustained p38 MAPK activation. Roger et al. [76] demonstrated the negative regulation of GC-induced MKP-1 by rMIF in the RAW 264.7 macrophage cell line. MIF therefore inhibits GC-induced expression of anti-inflammatory MKP-1, and thus inhibits the de-phosphorylation of MAPKs, in particular phospho-p38 [75] (Fig. 1). Phospho-p38 MAPK regulates cytokine expression either post-transcriptionally via regulation of mRNA stabilization and translation, or at the level of transcription via activation of AP-1 [83, 84]. The net effect is that the presence of MIF limits the ability of GC to induce the expression of a molecule essential to their therapeutic effects. The observations that p53 is a direct transactivator of MKP-1, and that p53 is inhibited by MIF, provides a hypothetical mechanism for the inhibition of MKP-1 expression by MIF, which remains untested [85].


Figure 1
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  		FIG. 1. Inhibitory effects of MIF on GC-induced transactivation. GC binds to the cytosolic glucocorticoid receptor (GR), which translocates as a homodimer to the nucleus to engage glucocorticoid response elements (GRE) on the promoter region of anti-inflammatory genes such as MKP-1. MIF inhibits GC-induced transactivation of MKP-1, thereby leading to a reduced ability to inactivate MAPKs such as phospho-p38 MAPK (p-p38). Whether MIF directly influences MKP-1, or does so via effects on p53, which is a transactivator of MKP-1, is not known.

 
Alternative mechanisms for the effects of MIF GC-sensitivity
Another candidate gene for MIF effects on GR-mediated transactivation is I{kappa}B-{alpha}. In order for NF-{kappa}B to enter the nucleus, its site of action, the cytoplasmic NF-{kappa}B:I{kappa}B complex needs to be disrupted. I{kappa}B-{alpha} belongs to a family of I{kappa}Bs, which bind to NF-{kappa}B dimers and sterically block the function of a nuclear localization sequence, thereby causing their cytoplasmic retention [86]. I{kappa}B-{alpha} acts therefore as a direct inhibitor of the NF-{kappa}B pathway [87]. Direct effects of MIF on transactivation or phosphorylation of I{kappa}B-{alpha} have not been reported. However, MIF was reported to impair GC-induced transactivation of I{kappa}B-{alpha} in human mononuclear cells [50].

The expression of the immunomodulatory (anti-inflammatory) cytokine IL-10 is also known to be transcriptionally up-regulated by GC [88]. Interestingly IL-10 has previously been shown to inhibit the release of MIF [89]. MIF, in contrast, has been shown to induce the synthesis and expression of intracellular IL-10 as well as surface expression of IL-10 receptors [90]. Such an effect of MIF would not be expected to contribute to its GC-antagonistic effects, but there are no studies that directly examine MIF effects on IL-10 expression under the influence of GCs. Similarly, there are no reports of effects of MIF on the GC-induced anti-inflammatory protein annexin-1.

The breadth of GC actions in suppression of inflammation has been previously related to GC transrepression of pro-inflammatory genes [91–94]. Transrepression is indirectly mediated, and does not require binding of the GC-activated GR to DNA. Rather, the GC–GR complex modulates the action of other transcription factors such as activator protein (AP)-1 or NF-{kappa}B, which are essential for the regulation of gene expression during inflammation [95]. The expression of cytokines, chemokines, adhesion molecules and enzymes (such as cyclooxygenase-2) are regulated by these transcription factors, and as such their expression is potently inhibited by direct interactions with and the GC-occupied GR monomer [95–97]. AP-1 overexpression has been associated with GC-resistance in asthma [98]. MIF may antagonize the transrepressive effect of GC on AP-1 via its capacity to activate MAPK pathways, thereby providing a drive to the activation of AP-1 (Fig. 2). The activation of MAPKs by MIF has been confirmed in cell types relevant to RA. In osteoblasts, for example, MIF activates ras-related GTPase, rac and protein kinase C in ERK MAPK activation, and c-fos and c-jun mRNA components of AP-1 [68]. In RA synovial fibroblasts, MIF activates both ERK and p38 MAP kinase [48, 51], both of which are capable of impacting on AP-1.


Figure 2
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  		FIG. 2. Antagonistic effects of MIF on GC-induced transrepression. GC binds to the GR monomer, translocates to the nucleus and inhibits the activity of AP-1 and NF-{kappa}B. MIF in contrast activates MAPKs pathways, which in turn activate AP-1. MIF and GC-bound GR effect a balance between activation and deactivation of AP-1.

 

   Potential toxicity of MIF antagonism
Top
 Abstract
 Introduction
 Macrophage migration inhibitory...
 The role of MIF...
 MIF and GCs
 Potential toxicity of MIF...
Conclusions
 References
 
The development of MIF antagonists for clinical applications including steroid-sparing is being pursued by several biotechnology companies, mandating consideration of possible toxicity of MIF antagonism, especially relative to the toxicity of GC. GCs have significant harmful effects on bone, atherosclerosis and diabetes. The available evidence suggests that MIF antagonism would be protective from, rather than additive to, these events. MIF up-regulates MMP-13, a key enzyme in bone resorption, more potently than does PTH [68], and a favourable effect of MIF deficiency on ovariectomy-induced bone loss supports a bone-protective effect of MIF antagonism [42]. Up-regulation of MIF production has been observed in vascular endothelial cells, vascular smooth muscle cells and macrophages/foam cells during the progression of atherosclerotic plaque evolution in humans [99] and MIF depletion has been shown to be protective in models of atheroma [38, 100]. Finally, features of diabetic disease as hyperglycaemia and insulitis are reduced by the administration of MIF antagonists [101, 102].

Since MIF regulates immunity, a potential effect on infection risk upon MIF blockade would require investigation. MIF–/– mice tolerate routine housing without evidence of opportunistic infections or delayed wound healing. Evidence of increased susceptibility of MIF-deficient mice to infection with Leishmania major [103] as well as higher susceptibility and higher parasite load of the helminth Taenia crassiceps [104] and the worm Schistosoma japonicum [90] reflect the potential risk of immunosuppression due to MIF antagonism. However, the profile of MIF antagonist treatment may be different to that of a genetically modified MIF-deficient mouse. Moreover, the lack of effect of MIF on NF-{kappa}B activation [49, 51] suggests a differentiated infection risk profile compared with TNF or IL-1 blockade. A further potential contrast to TNF blockade is in relation to cancer risk. For example, MIF antagonism has been shown to be protective in a model of lymphoma [60]. Expression of MIF is increased in colon cancers [105, 106], and deletion of MIF is associated with reduction in the number and size of colon adenomas and angiogenesis [107]. The net effect of MIF antagonism on cancer, therefore, is predicted to be inhibitory, and indeed this is being investigated as a direct application for MIF antagonists.


   Conclusions
Top
 Abstract
 Introduction
 Macrophage migration inhibitory...
 The role of MIF...
 MIF and GCs
 Potential toxicity of MIF...
 Conclusions
References
 
MIF is a pro-inflammatory cytokine that functions as a physiological counter-regulator of the anti-inflammatory effects of GC, and MIF is now known to regulate sensitivity to GC via modulation of the expression of MKP-1. This suggests a mechanism that could be exploited therapeutically. MIF antagonism could be achieved through monoclonal antibody treatment or conceivably through the development of small molecule direct MIF antagonists. By selectively limiting the effect of a protein that impedes the anti-inflammatory effects of GC, MIF antagonism could specifically augment steroid actions, thereby providing the first definitive steroid-sparing therapy.

The authors have declared no conflicts of interest.


   Acknowledgments
 
D.A. is supported by grants from Novartis, the Albert Böni Foundation, Switzerland, and the Swiss Foundation for Research in Medicine and Biology. E.M. and M.L. are supported by grants from the National Health and Medical Research Council, Australia, and National Institutes of Health, USA.


   References
Top
 Abstract
 Introduction
 Macrophage migration inhibitory...
 The role of MIF...
 MIF and GCs
 Potential toxicity of MIF...
 Conclusions
 References
 

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Submitted 2 November 2005; revised version accepted 27 February 2006.
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