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J Nishihira

Publications and source records attributed to J Nishihira.

At least 19 recordsLinked to original sources
PubMed2006

Role of macrophage migration inhibitory factor in ovalbumin-induced airway inflammation in rats.

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that reportedly counteracts the anti-inflammatory effect of endogenous glucocorticoids. There have only been a few reports that demonstrate a potential link between MIF and bronchial asthma. In an attempt to further clarify the precise role of MIF in asthma, the present authors examined the effect of anti-MIF antibody (Ab) on airway inflammation and airway hyperresponsiveness in an ovalbumin-immunised rat asthma model. Actively immunised Brown Norway rats received ovalbumin inhalation with or without treatment of anti-MIF Ab. The levels of MIF in bronchoalveolar lavage fluid were significantly elevated after the ovalbumin challenge. An immunohistochemical study revealed positive immunostaining for MIF in bronchial epithelium, even in nonsensitised rats, and the MIF staining in bronchial epithelium was enhanced after the ovalbumin challenge. Anti-MIF Ab significantly decreased the number of total cells, neutrophils and eosinophils in the bronchoalveolar lavage fluid of the ovalbumin-challenged rats, and also attenuated the ovalbumin-induced airway hyperresponsiveness to ovalbumin and methacholine. However, anti-MIF Ab did not affect the level of serum ovalbumin-specific IgE, suggesting that anti-MIF Ab did not suppress immunisation itself. The results indicate that macrophage migration inhibitory factor plays a crucial role in airway inflammation and airway hyperresponsiveness in asthma.

Animals↗
PubMed2006

Promoter polymorphism in the macrophage migration inhibitory factor gene is associated with obesity.

OBJECTIVE: To explore the association of promoter polymorphisms of macrophage migration inhibitory factor (MIF) gene with obesity. SUBJECTS: In total, 213 nondiabetic Japanese subjects. They were divided into three groups according to World Health Organization definitions: lean (body mass index (BMI) <25 kg/m2), overweight (25 < or = BMI < 30 kg/m2) and obese (BMI> or = 30 kg/m2). METHODS: We examined two polymorphic loci in the MIF gene in the subjects: a single-nucleotide polymorphism at position -173 (G/C) and a CATT-tetranucleotide repeat polymorphism at position -794, which both can affect promoter activity in different cells. RESULTS: We detected four alleles: 5-, 6-, 7- and 8-CATT at position -794. Genotypes without the 5-CATT allele (X/X, X refers to 6-, 7- or 8-CATT alleles) were more common in obese subjects than in lean or overweight groups (P = 0.013). The X-CATT allele was more frequent in obese subjects than in lean or overweight subjects (P = 0.030). In contrast, -173G/C was not associated with obesity. Among the haplotypes of the two promoter polymorphisms, G/5-CATT ((-173G/C)/(-794[CATT](5-8))) was associated with a decreased risk of obesity (P = 0.025) and G/6-CATT with an increased risk of overweight (P=0.028). CONCLUSION: Promoter polymorphism in the MIF gene is linked with obesity.

Adult↗
PubMed2005

Role for macrophage migration inhibitory factor in asthma.

Macrophage migration inhibitory factor (MIF) is an immunologic regulator that is expressed in inflammatory and autoimmune disorders. We investigated MIF's role in asthma using genetic approaches in a mouse model and in a cohort of asthma patients. Mice genetically deficient in MIF that were primed and aerosol-challenged with ovalbumin showed less pulmonary inflammation and lower airway hyperresponsiveness than genetically matched, wild-type controls. MIF deficiency also resulted in lower titers of specific IgE, IgG(1), and IgG(2a), and decreased pulmonary, T(H)2 cytokine levels. IL-5 concentrations were lower and corresponded to decreased eosinophil numbers in bronchoalveolar lavage fluid. T cell studies also showed a lower level of antigen-specific responses in MIF-KO versus wild-type mice. In an analysis of 151 white patients with mild, moderate, or severe asthma (Global Initiative for Asthma criteria), a significant association was found between mild asthma and the low-expression, 5-CATT MIF allele. Pharmacologic inhibition of MIF may be beneficial and could be guided by the MIF genotype of affected individuals.

Adult↗
PubMed2005

Promoter region polymorphism of macrophage migration inhibitory factor is strong risk factor for young onset of extensive alopecia areata.

We have demonstrated that serum macrophage migration inhibitory factor (MIF) was significantly elevated in patients with extensive alopecia areata (AA). Recently, functional polymorphisms have been identified in the MIF promoter region. To address the functional and prognostic relevance of the -173G/C and -794[CATT]5-8 repeat polymorphisms in MIF genes in patients with extensive AA, 113 patients with extensive AA and 194 healthy controls were genotyped. We found that MIF-173*C was a risk factor for early onset (<20 years) of extensive AA (odds ratio for GC heterozygotes with -173G/C was 4.88 (95% CI, 2.04-11.8), P=0.00038; odds ratio for CC homozygotes with -173G/C was 10.42 (95% CI, 2.56-43.5), P=0.0011). We found no statistically significant differences in the genotype frequencies of the -794[CATT]5-8 repeat polymorphism and extensive AA. These results suggest that polymorphisms within the MIF-173*C allele confer an increased risk of susceptibility to the extensive forms of AA, especially with an early onset of disease. MIF is therefore suggested to be closely implicated in the pathogenesis of the more extensive forms of AA.

Adolescent↗
PubMed2005

Transgenic over-expression of macrophage migration inhibitory factor renders mice markedly more susceptible to experimental colitis.

Enhanced production of macrophage migration inhibitory factor (MIF) is recognized in patients with inflammatory bowel disease (IBD) and mice with experimental colitis; however, the precise molecular function of MIF in colitis is not fully understood. To further investigate this matter, we examined the pathological features of MIF transgenic mice with dextran sulphate sodium (DSS)-induced colitis. We generated transgenic mice carrying a murine MIF cDNA driven by a cytomegalovirus enhancer and a beta-actin/beta-globin promoter. Mice were orally administered 1-4% DSS in drinking water for 7 days. Clinical disease activity, survival and histological features were evaluated. The level of myeloperoxidase (MPO) activity in the colon tissue was measured to assess neutrophil infiltration. The level of corticosterone in the serum was measured by enzyme linked-immunosorbent assay (ELISA). MIF mRNA and protein were markedly up-regulated in the colon and serum obtained from MIF transgenic mice. The severity of the colitis induced by 1% DSS treatment was markedly higher in MIF transgenic mice than in wild-type mice. We also found that MPO activity was significantly higher in MIF transgenic mice than wild-type mice in response to DSS stimulation. Interestingly, the corticosterone level remained unchanged in MIF transgenic mice. MIF enhances DSS-induced colitis, in part via neutrophil accumulation and inhibition of glucocorticoid bioactivity.

Animals↗
PubMed2005

Macrophage migration inhibitory factor contributes to the development of acute dextran sulphate sodium-induced colitis in Toll-like receptor 4 knockout mice.

Toll-like receptor 4 (TLR4), which recognizes lipopolysaccharides, plays an important role in the innate immune response. In this study, we investigated the role of TLR4 in the development of experimental colitis with regard to the biological actions of macrophage migration inhibitory factor (MIF) using TLR4 null ((-/-)) mice. TLR4(-/-) mice were given 2% dextran sulphate sodium (DSS) in drinking water to induce colitis, which was clinically and histologically as severe as that seen in wild-type (WT) mice. The level of tumour necrosis factor (TNF)-alpha in colon tissues was increased in WT mice but unchanged in TLR4(-/-) mice. The level of myeloperoxidase (MPO) activity in colon tissues was increased by DSS administration in both TLR4(-/-) and WT mice. The expression of MIF was up-regulated in the colons of TLR4(-/-) mice with acute DSS-induced colitis. An anti-MIF antibody significantly suppressed colitis and elevation of matrix metalloproteinase-13 in TLR4(-/-) mice. The current results obtained from TLR4(-/-) mice provide evidence that MIF plays a critical role in the development of acute DSS-induced colitis.

Acute Disease↗
PubMed2004

Cetirizine, an H1-receptor antagonist, suppresses the expression of macrophage migration inhibitory factor: its potential anti-inflammatory action.

BACKGROUND: H1-receptor antagonists are often effective in the treatment of allergic disorders such as atopic dermatitis. Cetirizine, a putative H1-receptor antagonist, has recently been shown to have anti-inflammatory properties through the inhibition of leucocyte recruitment and activation, and by the reduction of ICAM-1 expression on keratinocytes. OBJECTIVE: To further elucidate the anti-inflammatory properties of cetirizine, we first examined its effects on antigen-induced eosinophilia and neutrophila in vivo. We then examined the anti-inflammatory effects of cetirizine on a human keratinocyte A431cell line. METHODS: Mice were sensitized subcutaneously with ragweed pollen and were challenged intraperitoneally with the allergen. Cetirizine diluted in sterile water (0-20 mg/kg) or only sterile water was administered orally. Peritoneal cells were obtained at 8 and 24 h after challenge. The eosinophilia and neutrophilia induced by ragweed pollen extract were quantitated. Macrophage migration inhibitory factor (MIF), macrophage inflammatory protein 2 (MIP-2) and eotaxin contents of peritoneal fluid were also measured by mouse ELISA. The effects of cetirizine on MIF-induced IL-8 production in A431 cells were examined by ELISA. The effects of cetirizine on MIF expression and production in A431 cells were examined by human MIF ELISA and Northern blot analysis. RESULTS: Eosinophilia and neutrophilia induced by ragweed pollen extract were found to be significantly reduced in cetirizine-treated mice (20 mg/kg). MIF, a pleuripotent cytokine, was significantly decreased at 8 and 24 h in the peritoneal fluid by cetirizine treatment. MIP-2 and eotaxin were also decreased 8 and 24 h, respectively, after challenge in the peritoneal fluid with cetirizine treatment. MIF stimulates IL-8 production in A431 cells. We found that MIF production in A431 cells was inhibited by 10 microm cetirizine. Consistent with this, cetirizine significantly inhibited MIF-induced IL-8 production. CONCLUSION: These results suggest that cetirizine exerts its anti-inflammatory effects by inhibiting MIF as well as IL-8 production, such as those involved in inflammatory allergic skin disease, suggesting a broad spectrum of action beyond its mere H1-receptor-antagonistic function.

Allergens↗
PubMed2004

Aqueous levels of macrophage migration inhibitory factor and monocyte chemotactic protein-1 in patients with diabetic retinopathy.

AIMS: To investigate the relationship of aqueous macrophage migration inhibitory factor (MIF) and monocyte chemotactic protein-1 (MCP-1) levels with the clinical stage of diabetic retinopathy. METHODS: We assayed MIF and MCP-1 levels in aqueous humour samples obtained from 40 diabetic patients (49 eyes) and 24 non-diabetic patients (31 eyes) using enzyme-linked immunosorbent assay. According to the clinical stage of diabetic retinopathy, the diabetic patients were classified into non-diabetic retinopathy (11 eyes), non-proliferative diabetic retinopathy (14 eyes) and proliferative diabetic retinopathy (24 eyes). RESULTS: The aqueous levels of MIF (mean +/- sd) were 6.34 +/- 4.53 ng/ml in proliferative diabetic retinopathy, 3.22 +/- 1.71 ng/ml in non proliferative diabetic retinopathy, 1.25 +/- 0.96 ng/ml in non-diabetic retinopathy and 1.07 +/- 0.94 ng/ml in non-diabetic patients. Significant differences were found among these four groups (P < 0.0001). Aqueous MCP-1 levels were 1668.6 +/- 1442.3 pg/ml in proliferative diabetic retinopathy, 1528.6 +/- 1994.6 pg/ml in non-proliferative diabetic retinopathy, 690.2 +/- 402.1 pg/ml in non-diabetic retinopathy and 622.7 +/- 245.3 pg/ml in non-diabetic patients. Significant differences were also found among these four groups (P < 0.0001). After correcting for total aqueous protein, the ratios of MIF and MCP-1 to total protein remained significantly correlated with the clinical stage of diabetic retinopathy (P < 0.0001, P = 0.0004, respectively). The ratios of MIF to total protein significantly correlated with the ratios of MCP-1 to total protein in diabetic patients (r = 0.680, P < 0.0001). CONCLUSIONS: Aqueous MIF levels significantly correlated with aqueous MCP-1 levels and the clinical stage of diabetic retinopathy. The results suggest that MIF has a co-operative role with MCP-1 in the progression of diabetic retinopathy.

Adult↗
PubMed2003

Immunohistochemical study of macrophage migration inhibitory factor in rat liver fibrosis induced by thioacetamide.

Macrophage migration inhibitory factor (MIF) is a molecule known to regulate macrophage accumulation at sites of inflammation. To elucidate the role of MIF in progression of liver fibrosis, the immunohistochemical localization of MIF and macrophages in the liver were examined. Male Wistar rats received thioacetamide (TA) injections (200 mg/kg, i.p.) for 1 or 6 weeks. In biochemical and histological tests, it was confirmed that liver fibrosis was induced. In immunohistochemical analyses, the expression of MIF protein was seen in hepatocytes in the areas extending out from the central veins to the portal tracts. In particular, at 6 weeks, immunoreactivity was detected in degenerated hepatocytes adjacent to the fibrotic areas but hardly observed in the fibrotic areas. On the other hand, a number of exudate macrophages stained by antibody ED1 were seen in the areas from the central veins to the portal tracts at 1 week and in the fibrotic areas at 6 weeks. Macrophages also showed a significant increase in number as compared with controls. These results revealed that there was a close relationship between the appearance of MIF expression and ED1-positive exudate macrophages in degenerated hepatocytes during the progression of TA-induced liver fibrosis.

Animals↗
PubMed2001

Suppression of GST-P by treatment with glutathione-doxorubicin conjugate induces potent apoptosis in rat hepatoma cells.

A conjugate of doxorubicin and glutathione via glutaraldehyde (GSH-DXR) inhibited glutathione S-transferase (GST) activity of rat hepatoma AH66 cells, and treatment of the cells with GSH-DXR induced caspase-3 activation and DNA fragmentation. After treatment of AH66 cells with 0.1 microM GSH-DXR, GST-P (placental type of rat GST isozymes) mRNA and its protein increased transiently and then decreased thereafter compared with the levels in nontreated cells. Caspase-3 activation and DNA fragmentation were induced following the suppression of GST-P expression by treatment with GSH-DXR. When the cells were treated with 100 microM ethacrynic acid (ECA), an inhibitor of GST, DNA fragmentation and caspase-3 activation were observed. In contrast, treatment of AH66 cells with a low concentration of ECA (1 microM) that showed little inhibition of GST activity induced slight, but significantly enhanced expression and activity of GST-P, and consequent prevention of DXR- and GSH-DXR-induced DNA fragmentation. Overexpression of GST-pi (placental type of human GST isozymes) by transfection of GST-pi sense cDNA into AH66 cells decreased sensitivities to DXR and GSH-DXR, and the suppression of GST-P by transfection of the antisense cDNA into the cells increased drug sensitivity. On the other hand, there was little change in drug sensitivity caused by overexpression of site-directedly mutated GST-P in which the active-site residue Tyr39 was replaced with His (W39H) or the substrate-binding site residue Cys48 was replaced with Ser (C48S) by transfection of those cDNAs into AH66 cells. These results suggested that the suppression of GST-P in AH66 cells treated with GSH-DXR must play an important role in the induction of apoptosis.

Animals↗
PubMed2001

Expression, purification, crystallization and preliminary X-ray diffraction analysis of the human calcium-binding protein MRP14 (S100A9).

MRP14 is a protein that is specifically expressed in myeloid and epithelial cells during the stages of acute or chronic inflammatory states such as rheumatoid arthritis or sarcoidosis. MRP14 has EF-hand motifs as Ca(2+)-binding sites and belongs to the S100 family of proteins. This paper deals with the sample preparation (cloning, overexpression and purification), crystallization and preliminary crystallographic analysis of recombinant human MRP14. Crystals of MRP14 were obtained by the hanging-drop vapour-diffusion method. MRP14 crystals belong to space group P2(1), with unit-cell parameters a = 57.59, b = 178.44, c = 61.23 A, beta = 113.17 degrees, and diffract to 2.1 A resolution.

Amino Acid Sequence↗
PubMed2001

Macrophage migration inhibitory factor is a critical mediator of systemic inflammatory response syndrome.

OBJECTIVE: To determine the relations between macrophage migration inhibitory factor (MIF), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and cortisol in patients with systemic inflammatory response syndrome (SIRS) and to determine whether their levels correlate with patient survival. DESIGN: Prospective, observational, cohort study. SETTING: General intensive care unit in a university hospital. PATIENTS AND PARTICIPANTS: The study included 17 consecutive patients who met the criteria for SIRS; the patients were classified into subgroups, survivors (n = 8) and nonsurvivors (n = 9); eight healthy volunteers served as control subjects. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Serum MIF, TNF-alpha, IFN-gamma, and cortisol levels were measured serially when the patients were first identified as having SIRS (day 0), and on days 1-4. Except for the high tendency of acute respiratory distress syndrome in nonsurvivors (44%) compared to survivors (13%), there were no differences in the clinical backgrounds of the patients between the two groups. All patients had multiple organ dysfunction syndrome. The values of MIF and TNF-alpha in the nonsurvivors were significantly more elevated than those cytokines measured in the survivors and control subjects. Peak MIF levels significantly correlated with peak TNF-alpha levels (r2 = 0.448, P = 0.002), but did not correlate with peak levels of cortisol and IFN-gamma. Although the levels of IFN-gamma and cortisol showed a marked increase compared to those of the control subjects, we could not find differences in these variables between the survivors and the nonsurvivors. CONCLUSIONS: High MIF and TNF-alpha levels are closely linked with poor outcome in patients with SIRS. MIF and TNF-alpha may act together and have pathogenic roles in SIRS.

Adult↗
PubMed2001

Systemic macrophage migration inhibitory factor release following hepatic resection.

We set out to determine the responses of macrophage migration inhibitory factor (MIF) to hepatic resection and investigate its role in predicting short-term postoperative morbidity and outcome. Blood samples from 29 patients undergoing hepatic resection and eight healthy volunteers were obtained serially for 24h and assayed for serum MIF, cortisol, and tumor necrosis factor (TNF)-alpha. The MIF and cortisol levels showed a parallel increase and their peak levels were significantly correlated (r2 = 0.33, P = 0.0011). The TNF-alpha levels also increased during and after hepatic resection, but did not correlate with the MIF levels. The patients were classified into an extended hepatectomy group (n = 9); a lobectomy/segmentectomy group (n = 12); and a subsegmentectomy group (n = 8). There were no differences in the time courses of MIF (P = 0.8699), cortisol (P = 0.7485), and TNF-alpha (P = 0.3819) among the three groups. No patients developed organ dysfunction and all were discharged from the intensive care unit without any complications. Our findings demonstrate that MIF production occurs in patients undergoing hepatic resection. Surgical stress may play a more important role in MIF secretion than inflammatory stimulus by TNF-alpha in these patients. Therefore, MIF minimally affects short-term postoperative morbidity and outcome.

Analysis of Variance↗
PubMed2001

Macrophage migration inhibitory factor as a redox-sensitive cytokine in cardiac myocytes.

OBJECTIVE: Macrophage migration inhibitory factor (MIF), which plays a pivotal role in the control of inflammatory responses, was first characterized as a T-cell cytokine, but later was also found as a pituitary peptide released in response to infection and stress. However, MIF's role and expression in the myocardium has never been reported. The goal of this study is to examine MIF in the myocardium. METHODS AND RESULTS: MIF protein and mRNA levels were assayed using enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR), respectively. Increased MIF concentrations were detected in the sera of patients with acute myocardial infarction (AMI). In cultured rat cardiac myocytes, significant amounts of MIF were produced in response to hypoxia and hydrogen peroxide (H(2)O(2)), but not to angiotensin II, endothelin-1, interleukin-1beta (IL-1beta) or tumor necrosis factor alpha (TNFalpha). H(2)O(2)-induced MIF production increased in a time- and dose-dependent manner and was completely abolished in the presence of catalase. H(2)O(2) also induced MIF mRNA expression. The H(2)O(2)-induced MIF production was completely inhibited by the protein kinase C (PKC) inhibitor GF109203X, partially inhibited by the tyrosine kinase inhibitor herbimycin A, and uninhibited by calcium chelation or phorbol ester-sensitive PKC down-regulation. This suggests that H(2)O(2)-induced MIF production is mediated by an atypical PKC isoform. DNA microarray analysis revealed that 52 genes were preferentially expressed in response to MIF. Of these, the MIF-induced expression of both glutathione S-transferase (GST) and lipopolysaccharide-induced CXC chemokine (LIX) mRNAs was confirmed using RT-PCR analysis. CONCLUSION: The present results suggest that MIF is expressed by the myocardium in response to redox stress and may play a role in the pathogenesis of myocardial ischemia.

Analysis of Variance↗
PubMed2001

Effect of coffee consumption on bone metabolism.

The effects of coffee on bone metabolism are still controversial, although several studies have suggested that caffeine and/or heavy coffee consumption is associated with a significant increase in risk of fracture, osteoporosis, and periodontal disease. Therefore, we sought to clarify the relationship between coffee consumption and bone metabolism using male Wistar rats. Forty-eight male Wistar rats were assigned to three treatment groups including a control-diet group (control, n = 16, coffee-free diet), a 0.62% coffee-diet group (low caffeine, n = 16, diet supplemented with 6.2 g/kg of the control diet), and a 1.36% coffee-diet group (high caffeine, n = 16, diet supplemented with 13.6 g/kg of the control diet), and animals were maintained on an experimental diet for 140 days. Although caffeine in serum was not detected in rats fed the control diet, low-intake coffee for 140 days led to an increase in caffeine concentration to 0.53 +/- 0.11 microg/mL and high-intake coffee led to an increase of 1.77 +/- 0.22 microg/mL. No significant differences in body weight change, serum and urinary biochemical markers of bone metabolism, and bone histomorphometry were found between the coffee-diet groups and the control-diet group, except that urinary phosphorus excretion after 140 days of both coffee diets was significantly increased compared with controls (p < 0.05). In addition, the coffee diets were not associated with differences in tumor necrosis factor-alpha and interleukin-6, which have been implicated in the pathogenesis of bone loss together with interleukin-1beta. In conclusion, the present study strongly indicates that coffee does not stimulate bone loss in rats.

Amino Acids↗
PubMed2001

Macrophage migration inhibitory factor in ocular fluids of patients with uveitis.

AIMS: To investigate the levels of macrophage migration inhibitory factor (MIF) in intraocular fluids of uveitis patients, the capacity of intraocular infiltrating lymphocytes to produce MIF, and the correlation between MIF levels in the eye and intraocular inflammatory activity. METHODS: MIF levels were measured by enzyme linked immunosorbent assay (ELISA) using (1) aqueous humour (AH) of 12 uveitis patients and eight control patients with cataract, (2) vitreous fluid of 15 uveitis patients and eight control patients with idiopathic macular hole, and (3) culture supernatants of T cell clones (TCCs) established from intraocular fluids of uveitis patients. MIF expression on infiltrating cells was determined by a double staining immunofluorescence technique using a flow cytometry. RESULTS: Significant levels of MIF were detected from intraocular fluids of uveitis patients (4.0 (SD 3.0) ng/ml in AH and 16.5 (24.7) ng/ml in vitreous), whereas MIF levels in control groups were below the detectable levels. There was a significant correlation between MIF levels and vitreous inflammation (29.7 (30.0) ng/ml in active uveitis v 3.3 (2.6) ng/ml in inactive uveitis, p< 0.05). Significant levels of MIF were detected in culture supernatants of TCCs from ocular fluids of uveitis patients. MIF was expressed on infiltrating CD4+ lymphocytes from vitreous of uveitis patients. CONCLUSION: Significant levels of MIF are present in intraocular fluids of patients with uveitis. Lymphocytes infiltrating in the eye are capable of producing MIF. MIF levels in vitreous fluid are correlated with vitreous inflammation activity. These data thus indicate that MIF in the eye has a significant role in the pathophysiology of ocular inflammation.

Adult↗