Gregory, J. L. et al. Reduced leukocyte-endothelial cell interactions in the inflamed microcirculation of macrophage migration inhibitory factor-deficient mice. Arthritis Rheum. 50, 3023-3034

Centre for Inflammatory Diseases, Monash University, Victoria, Australia.
Arthritis & Rheumatology (Impact Factor: 7.76). 09/2004; 50(9):3023-34. DOI: 10.1002/art.20470
Source: PubMed


Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with established roles in a range of inflammatory conditions. However, it is not known whether MIF influences inflammation via the direct promotion of leukocyte-endothelial cell interactions. Therefore, the aim of these experiments was to investigate the ability of MIF to regulate leukocyte-endothelial cell interactions in the inflamed microvasculature.
Intravital microscopy was used to examine postcapillary venules in the cremaster muscle and synovium of wild-type and MIF(-/-) mice. Leukocyte-endothelial cell interactions (rolling, adhesion, emigration) were compared under a range of inflammatory conditions.
In cremasteric postcapillary venules of MIF(-/-) mice, lipopolysaccharide (LPS)-induced leukocyte rolling, adhesion, and emigration were significantly reduced relative to that in wild-type mice. Similar responses were observed in response to tumor necrosis factor alpha and histamine. Examination of the synovial microvasculature following exposure to carrageenan revealed that leukocyte rolling and adhesion in synovial postcapillary venules and leukocyte entry into the joint space were also reduced significantly in MIF(-/-) mice. In each of these models, the level of P-selectin-dependent rolling was reduced in MIF(-/-) mice. Despite this, no difference in P-selectin expression was observed following LPS treatment. However, microvascular shear forces were elevated in MIF(-/-) mice, raising a possible mechanism to explain the reduced interactions in these animals.
MIF(-/-) mice consistently displayed a reduction in P-selectin-dependent rolling, suggesting that MIF exerts proinflammatory effects, in part, via the promotion of P-selectin-mediated rolling. Together, these data indicate that MIF promotes interactions between leukocytes and endothelial cells, thereby enhancing the entry of leukocytes into sites of inflammation.

Download full-text


Available from: Yuan Yang, Mar 17, 2015
    • "Macrophage migration inhibitory factor (MIF) is a cytokine with versatile functions including promotion of immune response, regulation of glucose metabolism and glucocorticoid action. MIF predominantly stimulates cell of innate immune system such as macrophages to exert their antimicrobial function (Roger et al., 2013; Stojanovic et al., 2011) or neutrophils to reach the site of microbial attack (Gregory et al., 2004). Also, MIF-deficient mice exert strong anti-inflammatory phenotype since their activated immune cells express or secrete lower amounts of proinflammatory mediators (IFN-γ, IL-17, IL-23, IL-1β) and higher levels of anti-inflammatory cytokines (Gao et al., 2011; Stojanovic et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Macrophage migration inhibitory factor (MIF)-deficient mice develop glucose intolerance and hyperglycemia, but remain entirely responsive to exogenous insulin in adult age. Furthermore, as a consequence of MIF deficiency, the immune response in these mice is predominantly anti-inflammatory. Since MIF is a natural counter-regulator of glucocorticoid action, and it is known that excessive concentration of glucocorticoids contribute both to beta cell dysfunction and immunosuppression, we hypothesized that MIF absence enables elevation of glucocorticoids which in turn caused the observed condition. Our results confirm that MIF-knockout (MIF-KO) mice possess higher levels of circulating corticosterone, but lower expression of glucocorticoid receptor in pancreatic islets, liver and adipose tissue to the one observed in wild type (WT) mice. A significant up-regulation of glucocorticoid receptor expression was however noticed in MIF-deficient lymph node cells. The inhibition of glucocorticoid receptor by RU486 improved tolerance to glucose in MIF-KO mice and restored euglycemia. Although RU486 treatment did not alter the level of glucose receptor GLUT2, it enhanced insulin secretion and up-regulated insulin-triggered Akt phosphorylation within hepatic tissue. Finally, inhibition of glucocorticoid receptor changed anti-inflammatory phenotype of MIF-KO lymphocytes toward a physiological profile. Our results indicate that deregulated glucocorticoid secretion and glucocorticoid receptor expression in the absence of MIF possibly contributes to the development of glucose intolerance and immunosuppression in MIF-KO mice. However, since MIF-KO mice respond normally to insulin and their beta cell function is within physiological range, additional cause for glucose intolerance could be sought in the possible malfunction of their insulin.
    European journal of pharmacology 07/2013; 714(1-3). DOI:10.1016/j.ejphar.2013.06.037 · 2.53 Impact Factor
  • Source
    • "In the present study, we demonstrated that the genetic variants of MIF, including the 7-repeat variant of the CATT STR, the C allele of the G-173C SNP, and the haplotype composed of the two alleles, are associated with an increase in the severity of carotid plaques in patients with ischemic stroke. MIF has been shown to participate in critical steps of the development of atherosclerotic lesions, including promoting leukocyte adhesion and infiltration [25], uptake of oxidized low-density lipoprotein [26], cytokine secretion [11], the expression of matrix metalloproteinases [27], T cell activation , [12] and the migration of vascular smooth muscle cells [28]. The expression of MIF in the lesions is up-regulated along with the progression of atherosclerosis [10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Atherosclerosis is a chronic inflammatory disorder. Macrophage migration inhibitory factor (MIF) is a potent cytokine that plays an important role in the regulation of immune responses. Polymorphisms including five- to eight-repeat CATT variants ((CATT)5-8) and G-173C in the promoter region of the MIF gene are associated with altered levels of MIF gene transcription. The purpose of the study is to investigate the relationship between promoter polymorphisms of the MIF gene and the severity of carotid artery atherosclerosis (CAA). The severity of CAA was assessed in 593 individuals with a history of ischemic stroke by using sonographic examination, and the MIF promoter polymorphisms of these individuals were genotyped. The carriage of (CATT)7 (compared to genotypes composed of (CATT)5, (CATT)6, or both), carriage of C allele (compared to GG), and carriage of the haplotype (CATT)7-C (compared to genotypes composed of (CATT)5-G, (CATT)6-G, or both) were significantly associated with an increase in the severity of CAA. We conclude that polymorphisms in the MIF gene promoter are associated with CAA severity in ischemic stroke patients. These genetic variants may serve as markers for individual susceptibility to CAA.
    Biochemical and Biophysical Research Communications 03/2013; 435(2). DOI:10.1016/j.bbrc.2013.02.129 · 2.30 Impact Factor
  • Source
    • "In response to a variety of stimuli, MIF is released from preformed intracellular stores through an ABC transporter-dependent export pathway [15]. MIF promotes the production of a number of proinflammatory moieties, such as TNF-α, IL-6, IL-12 and reactive oxygen species (ROS), and it is required for normal leukocyte influx into inflamed tissues 9,16,17. Elevated serum levels of MIF were detected in many infectious and inflammatory diseases, such as rheumatoid arthrits [18], sepsis [19], vasculopathy [20], viral hepatitis [21], HIV infection [22] and malaria [23], indicating that MIF is implicated in pathogenesis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Clinical symptoms of chronic Chagas disease occur in around 30% of the individuals infected with Trypanosoma cruzi and are characterized by heart inflammation and dysfunction. The pathogenesis of chronic chagasic cardiomyopathy (CCC) is not completely understood yet, partially because disease evolution depends on complex host-parasite interactions. Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine that promotes numerous pathophysiological processes. In the current study, we investigated the link between MIF and CCC progression. Immunohistochemical analysis demonstrated MIF overexpression in the hearts from chronically T. cruzi-infected mice, particularly those showing intense inflammatory infiltration. We also found that MIF exogenously added to parasite-infected murine macrophage cultures is capable of enhancing the production of TNF-α and reactive oxygen species, both with pathogenic roles in CCC. Thus, the integrated action of MIF and other cytokines and chemokines may account for leukocyte influx to the infected myocardium, accompanied by enhanced local production of multiple inflammatory mediators. We further examined by ELISA the level of MIF in the sera from chronic indeterminate and cardiomyopathic chagasic patients, and healthy subjects. CCC patients displayed significantly higher MIF concentrations than those recorded in asymptomatic T. cruzi-infected and uninfected individuals. Interestingly, increased MIF levels were associated with severe progressive Chagas heart disease, in correlation with elevated serum concentration of high sensitivity C-reactive protein and also with several echocardiographic indicators of left ventricular dysfunction, one of the hallmarks of CCC. Our present findings represent the first evidence that enhanced MIF production is associated with progressive cardiac impairment in chronic human infection with T. cruzi, strengthening the relationship between inflammatory response and parasite-driven pathology. These observations contribute to unravel the elements involved in the pathogenesis of CCC and may also be helpful for the design of novel therapies aimed to control long-term morbidity in chagasic patients.
    PLoS ONE 02/2013; 8(2):e57181. DOI:10.1371/journal.pone.0057181 · 3.23 Impact Factor
Show more