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Up-regulation of endometrial oxytocin receptor (OTR) expression followed by an increase in pulsatile endometrial prostaglandin (PG) F(2alpha) secretion causes luteolysis in cattle. Inhibition of luteolysis is essential for the maternal recognition of pregnancy but also occurs in association with endometritis. The factors regulating OTR expression at this time are unclear. The OTR gene promoter region contains binding elements for acute phase proteins but their function has not been established. This study investigated the effects of various cytokines on OTR expression and on PGF(2alpha) and PGE(2) production in explant cultures of bovine endometrium. Endometrium was collected in the late luteal phase (mean day of cycle 15.4+/-0.50) or early luteolysis (mean day of cycle 16.4+/-0.24) as determined by the initial concentration of endometrial OTR. Explants were treated for 48 h with: (i) lipopolysaccharide (LPS) and/or dexamethasone (DEX), (ii) ovine interferon-tau (oIFN-tau), or (iii) human recombinant interleukin (IL)-1alpha, -2 or -6. OTR mRNA was then measured in the explants by in situ hybridisation and the medium was collected for measurement of PGF(2alpha) and PGE(2) by RIA. LPS treatment stimulated production of PGF(2alpha), whereas DEX either alone or in combination with LPS was inhibitory to both PGF(2alpha) and PGE(2). Neither of these treatments altered OTR mRNA expression. oIFN-tau reduced OTR mRNA expression but stimulated production of both PGF(2alpha) and PGE(2). In endometrial samples collected in the late luteal phase, IL-1alpha, -2 and -6 all inhibited OTR mRNA expression, but IL-1alpha and -2 both stimulated PGF(2alpha) production. In contrast, when endometrium was collected in early luteolysis, none of the interleukins altered OTR expression or caused a significant stimulation of PGF(2alpha) production but IL-2 increased PGE(2). Neither IL-1alpha nor -2 altered OTR promoter activity in Chinese hamster ovary cells transfected with a bovine OTR promoter/chloramphenicol acetyl transferase reporter gene construct. In conclusion, the action of interleukins on both OTR mRNA expression and endometrial prostaglandin production alters around luteolysis. Pro-inflammatory interleukins suppress OTR expression in the late luteal phase, while LPS stimulates PGF(2alpha) without altering OTR mRNA expression. IL-I and -2 and LPS are therefore unlikely to initiate luteolysis but may cause raised production of PGF(2alpha) during uterine infection.
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The expression of oxytocin receptor (OTR) in the uterine endometrium plays an important role in the initiation of luteolysis. During early pregnancy, the conceptus secretes interferon tau (IFN|gt) which inhibits OTR up-regulation and luteolysis. In this study, uterine horn cross sections were collected on day 16 from 15 pregnant cows (PREG), 9 uninseminated controls and 5 inseminated cows with no embryo present. The latter two groups had similar results and were combined to form a single non-pregnant (NP) group. The animals were given an oxytocin challenge shortly before tissue collection to assess prostaglandin F2alpha (PGF2alpha) release through the measurement of the metabolite 13,14-dihydro-15-keto PGF2alpha (PGFM). The mRNAs for OTR, oestrogen receptor (ER) and progesterone receptor (PR) were localised by in situ hybridisation. The results were quantified by optical density (OD) measurements from autoradiographs using image analysis. OTR protein was measured by autoradiography with iodinated oxytocin antagonist and ER and PR protein was detected by immunocytochemistry. The release of PGFM after the oxytocin challenge was significantly higher in the 14 NP cows (187%+/-15%) compared with the PREG group (131%+/-11%) (P<0.01). Low concentrations of OTR mRNA were localised to the luminal epithelium (LE) in 6 out of the 14 NP cows, of which 2 also expressed OTR protein, while OTR mRNA and protein were undetectable in all the pregnant animals. These results indicated that the sampling time coincided with the onset of the luteolytic mechanism in the NP cows. On day 16 ER mRNA was detectable in both the LE and glands of both PREG and NP animals. There were no differences in either ER mRNA or protein between NP and PREG samples. PR mRNA was moderately expressed in the caruncular stroma, with lower levels in the dense caruncular-like stroma and glands. There were no differences between PREG and NP animals. The expression of PR mRNA and protein in the deep glands was variable between animals. These results suggested that, in cows, the presence of an embryo suppressed the expression of OTR, but had no effect on the expression of the transcriptionally regulated ER on day 16.
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Pancreases of untreated and nicotinamide (NIC)-treated pre-diabetic (10-week-old) and overtly diabetic (25-week-old) female NOD (non-obese diabetic) mice and of NON (non-obese non-diabetic) control mice were studied, with the following results. (1) Islets and ducts of overtly diabetic untreated NOD mice (25-week-old) were found to express low levels of MHC class I and II molecules, like NON controls, and high levels of adhesive molecules. (2) NIC was able to slightly affect glycaemia and insulitis, slowing down diabetes progression. Moreover it significantly decreased MHC class II expression (but not class I) in vivo by week 10, and significantly enhanced intercellular adhesion molecule-1 (ICAM-1) expression, mainly by week 25, within the pancreas, where 5-bromo-2'-deoxyuridine positive nuclei and insulin positive cells were present, demonstrating that a stimulation of endocrine cell proliferation occurs. (3) In addition, NIC partly counteracted the fall of superoxide dismutase levels, observed in untreated diabetic NOD animals. (4) In vitro studies demonstrated that NIC: (i) was able to significantly reduce nitrite accumulation and to increase NAD+NADH content significantly, and (ii) was able to increase the levels of interleukin-4, a T helper 2 lymphocyte (Th2) protective cytokine, and of interferon-alpha (IFN-alpha), which is known to be able to induce MHC class I and ICAM-1 but not MHC class II expression, as well as IFN-gamma, which is also known to be able to induce MHC class I and ICAM-1 expression. The latter, although known to be a proinflammatory Th1 cytokine, has also recently been found to exert an anti-diabetogenic role. This study therefore clearly shows that adhesive mechanisms are ongoing during the later periods of diabetes in pancreatic ducts of NOD mice, and suggests they may be involved in a persistence of the immune mechanisms of recognition, adhesion and cytolysis and/or endocrine regeneration or differentiation processes, as both NIC-increased ICAM-1 expression and 5-bromo-2'-deoxyuridine positivity imply. The effects of NIC on MHC class II (i.e. a reduction) but not class I, and, mainly, on ICAM-1 expression (i.e. an increase), together with the increase in Th2 protective cytokine levels are very interesting, and could help to explain its mechanism of action and the reasons for alternate success or failure in protecting against type 1 diabetes development.
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Interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) contribute to the initial stages of the autoimmune destruction of pancreatic beta cells. IL-1beta is released by activated macrophages resident within islets, and its cytotoxic actions include a stimulation of nitric oxide (NO) production and the initiation of apoptosis. Insulin-like growth factors (IGFs)-I and -II prevent apoptosis in non-islet tissues. This study investigated whether IGFs are cytoprotective for isolated islets of Langerhans from non-obese diabetic mice (NOD) mice exposed to cytokines. Pancreatic islets isolated from 5-6-week-old, pre-diabetic female NOD mice were cultured for 48 h before exposure to IL-1beta (1 ng/ml), TNF-alpha (5 ng/ml), IFN-gamma (5 ng/ml) or IGF-I or -II (100 ng/ml) for a further 48 h. The incidence of islet cell apoptosis was increased in the presence of each cytokine, but this was significantly reversed in the presence of IGF-I or -II (IL-1beta control 3.5+/-1.6%, IL-1beta 1 ng/ml 27.1+/-5.8%, IL-1beta+IGF-I 100 ng/ml 4.4+/-2.3%, P<0.05). The majority of apoptotic cells demonstrated immunoreactive glucose transporter 2 (GLUT-2), suggesting that they were beta cells. Islet cell viability was also assessed by trypan blue exclusion. Results suggested that apoptosis was the predominant cause of cell death following exposure to each of the cytokines. Co-incubation with either IGF-I or -II was protective against the cytotoxic effects of IL-1beta and TNF-alpha, but less so against the effect of IFN-gamma. Exposure to cytokines also reduced insulin release, and this was not reversed by incubation with IGFs. Immunohistochemistry showed that IGF-I was present in vivo in islets from pre-diabetic NOD mice which did not demonstrate insulitis, but not in islets with extensive immune infiltration. Similar results were seen for IGF-binding proteins (IGFBPs). These results suggest that IGFs protect pre-diabetic NOD mouse islets from the cytotoxic actions of IL-1beta, TNF-alpha and IFN-gamma by mechanisms which include a reduction in apoptosis.
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We examined whether 1,25 dihydroxyvitamin D(3) (1,25 D(3)), the active form of vitamin D involved in the regulation of the immune system, may also protect human pancreatic islet cells from destruction induced by cytokines. In this study, we specifically investigated the effect of 1,25 D(3) on oxidative stress and major histocompatibility complex (MHC) induction, both implicated in cytokine-induced islet cell dysfunction and destruction. We also investigated the effects of 1,25 D(3) on interleukin (IL)-6, a pleiotropic cytokine implicated in the pathogenesis of immunoinflammatory disorders. Human pancreatic islets, isolated from heart-beating donors, were treated with a combination of three cytokines, IL-1beta+tumor necrosis factor alpha+interferon gamma, in the presence or absence of vitamin D, and compared with with untreated control cells. Metabolic activity was assessed by cell viability and insulin content. Oxidative stress was estimated by heat shock protein 70 (hsp70) expression, cell manganese superoxide dismutase (MnSOD) activity and nitrite release, a reflexion of nitric oxide (NO) synthesis. Variation of immunogenicity of islet preparations was determined by analysis of the MHC class I and class II transcripts. Inflammatory status was evaluated by IL-6 production. After 48 h of contact with cytokines, insulin content was significantly decreased by 40% but cell viability was not altered. MHC expression significantly increased six- to sevenfold as well as NO and IL-6 release (two- to threefold enhancement). MnSOD activity was not significantly induced and hsp70 expression was not affected by the combination of cytokines. The addition of 1,25 D(3) significantly reduced nitrite release, IL-6 production and MHC class I expression which then became not significantly different from controls. These results suggest that the effect of 1,25 D(3) in human pancreatic islets cells may be a reduction of the vulnerability of cells to cytotoxic T lymphocytes and a reduction of cytotoxic challenge. Hence, 1,25 D(3) might play a role in the prevention of type 1 diabetes and islet allograft rejection.
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. 2016 ). In ruminant ungulates including cows, sheep and goats, interferon tau (IFNT), a major cytokine produced by mononucleate TE cells during the peri-implantation period, is the anti-luteolytic factor essential for the prolongation of CL life span
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Hooibrink B Brandts CH Nolte MA 2013 Interferon-γ impairs proliferation of hematopoietic stem cells in mice . Blood 121 3578 – 3585 . ( doi:10.1182/blood-2012-05-432906 ) Duque G Huang DC Macoritto M Rivas D Yang XF
Arthur G Janes Cancer Center and Richard J Solove Research Institute, Ohio State University, Columbus, Ohio 43210, USA
Unit of Immuno-oncology Aging Research Center, Ce.S.I., ‘Gabriele D’Annunzio’ University Foundation, Chieti-Pescara, Italy
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Edison Biotechnology Institute and Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701, USA
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Arthur G Janes Cancer Center and Richard J Solove Research Institute, Ohio State University, Columbus, Ohio 43210, USA
Unit of Immuno-oncology Aging Research Center, Ce.S.I., ‘Gabriele D’Annunzio’ University Foundation, Chieti-Pescara, Italy
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Edison Biotechnology Institute and Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701, USA
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Arthur G Janes Cancer Center and Richard J Solove Research Institute, Ohio State University, Columbus, Ohio 43210, USA
Unit of Immuno-oncology Aging Research Center, Ce.S.I., ‘Gabriele D’Annunzio’ University Foundation, Chieti-Pescara, Italy
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Edison Biotechnology Institute and Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701, USA
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Arthur G Janes Cancer Center and Richard J Solove Research Institute, Ohio State University, Columbus, Ohio 43210, USA
Unit of Immuno-oncology Aging Research Center, Ce.S.I., ‘Gabriele D’Annunzio’ University Foundation, Chieti-Pescara, Italy
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Edison Biotechnology Institute and Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701, USA
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Arthur G Janes Cancer Center and Richard J Solove Research Institute, Ohio State University, Columbus, Ohio 43210, USA
Unit of Immuno-oncology Aging Research Center, Ce.S.I., ‘Gabriele D’Annunzio’ University Foundation, Chieti-Pescara, Italy
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Edison Biotechnology Institute and Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701, USA
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Arthur G Janes Cancer Center and Richard J Solove Research Institute, Ohio State University, Columbus, Ohio 43210, USA
Unit of Immuno-oncology Aging Research Center, Ce.S.I., ‘Gabriele D’Annunzio’ University Foundation, Chieti-Pescara, Italy
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Edison Biotechnology Institute and Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701, USA
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Arthur G Janes Cancer Center and Richard J Solove Research Institute, Ohio State University, Columbus, Ohio 43210, USA
Unit of Immuno-oncology Aging Research Center, Ce.S.I., ‘Gabriele D’Annunzio’ University Foundation, Chieti-Pescara, Italy
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Edison Biotechnology Institute and Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701, USA
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Arthur G Janes Cancer Center and Richard J Solove Research Institute, Ohio State University, Columbus, Ohio 43210, USA
Unit of Immuno-oncology Aging Research Center, Ce.S.I., ‘Gabriele D’Annunzio’ University Foundation, Chieti-Pescara, Italy
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Edison Biotechnology Institute and Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701, USA
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Arthur G Janes Cancer Center and Richard J Solove Research Institute, Ohio State University, Columbus, Ohio 43210, USA
Unit of Immuno-oncology Aging Research Center, Ce.S.I., ‘Gabriele D’Annunzio’ University Foundation, Chieti-Pescara, Italy
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Edison Biotechnology Institute and Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701, USA
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, thymosin α1 and α,γ-interferons, also regulate MHC class I expressions in thyroid cells ( Saji et al. 1992 b , Giuliani et al. 2000 , Napolitano et al. 2000 , Grassadonia et al. 2004 ). We have previously defined the 5′ flanking region of
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Department of Animal Biology and Mari Lowe Center for Comparative Oncology Research, Cell and Molecular Biology Program, Department of Pathology, Inserm, Department of Cell Biology, Biomedical Graduate School, University of Pennsylvania, 380 S University Avenue, Philadelphia, Pennsylvania 19104, USA
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ubiquitination and subsequent degradation of PRLr ( Li et al . 2004 ). This mode of negative regulation has also been observed for other cytokine receptors including erythropoietin receptor (EpoR; Meyer et al . 2007 ) and Type I interferon receptor subunit
Department of Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
Translational Research Center, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Department of Internal Medicine, Social Insurance Funabashi Central Hospital, 6-13-10 Kaijin, Funabashi 273-8556, Japan
Department of Internal Medicine, Matsudo Municipal Hospital, 4005 Kamihongo, Matsudo 271-8511, Japan
Laboratory for Developmental Genetics, Riken Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
Department of Molecular Embryology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Department of Diabetes and Metabolic Disease, Asahi General Hospital, I-1136, Asahi 289-2511, Japan
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Department of Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
Translational Research Center, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Department of Internal Medicine, Social Insurance Funabashi Central Hospital, 6-13-10 Kaijin, Funabashi 273-8556, Japan
Department of Internal Medicine, Matsudo Municipal Hospital, 4005 Kamihongo, Matsudo 271-8511, Japan
Laboratory for Developmental Genetics, Riken Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
Department of Molecular Embryology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Department of Diabetes and Metabolic Disease, Asahi General Hospital, I-1136, Asahi 289-2511, Japan
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Department of Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
Translational Research Center, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Department of Internal Medicine, Social Insurance Funabashi Central Hospital, 6-13-10 Kaijin, Funabashi 273-8556, Japan
Department of Internal Medicine, Matsudo Municipal Hospital, 4005 Kamihongo, Matsudo 271-8511, Japan
Laboratory for Developmental Genetics, Riken Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
Department of Molecular Embryology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Department of Diabetes and Metabolic Disease, Asahi General Hospital, I-1136, Asahi 289-2511, Japan
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Department of Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
Translational Research Center, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Department of Internal Medicine, Social Insurance Funabashi Central Hospital, 6-13-10 Kaijin, Funabashi 273-8556, Japan
Department of Internal Medicine, Matsudo Municipal Hospital, 4005 Kamihongo, Matsudo 271-8511, Japan
Laboratory for Developmental Genetics, Riken Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
Department of Molecular Embryology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Department of Diabetes and Metabolic Disease, Asahi General Hospital, I-1136, Asahi 289-2511, Japan
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Department of Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
Translational Research Center, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Department of Internal Medicine, Social Insurance Funabashi Central Hospital, 6-13-10 Kaijin, Funabashi 273-8556, Japan
Department of Internal Medicine, Matsudo Municipal Hospital, 4005 Kamihongo, Matsudo 271-8511, Japan
Laboratory for Developmental Genetics, Riken Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
Department of Molecular Embryology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Department of Diabetes and Metabolic Disease, Asahi General Hospital, I-1136, Asahi 289-2511, Japan
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Department of Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
Translational Research Center, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Department of Internal Medicine, Social Insurance Funabashi Central Hospital, 6-13-10 Kaijin, Funabashi 273-8556, Japan
Department of Internal Medicine, Matsudo Municipal Hospital, 4005 Kamihongo, Matsudo 271-8511, Japan
Laboratory for Developmental Genetics, Riken Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
Department of Molecular Embryology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Department of Diabetes and Metabolic Disease, Asahi General Hospital, I-1136, Asahi 289-2511, Japan
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Department of Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
Translational Research Center, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Department of Internal Medicine, Social Insurance Funabashi Central Hospital, 6-13-10 Kaijin, Funabashi 273-8556, Japan
Department of Internal Medicine, Matsudo Municipal Hospital, 4005 Kamihongo, Matsudo 271-8511, Japan
Laboratory for Developmental Genetics, Riken Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
Department of Molecular Embryology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Department of Diabetes and Metabolic Disease, Asahi General Hospital, I-1136, Asahi 289-2511, Japan
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Department of Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
Translational Research Center, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Department of Internal Medicine, Social Insurance Funabashi Central Hospital, 6-13-10 Kaijin, Funabashi 273-8556, Japan
Department of Internal Medicine, Matsudo Municipal Hospital, 4005 Kamihongo, Matsudo 271-8511, Japan
Laboratory for Developmental Genetics, Riken Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
Department of Molecular Embryology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Department of Diabetes and Metabolic Disease, Asahi General Hospital, I-1136, Asahi 289-2511, Japan
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Department of Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
Translational Research Center, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Department of Internal Medicine, Social Insurance Funabashi Central Hospital, 6-13-10 Kaijin, Funabashi 273-8556, Japan
Department of Internal Medicine, Matsudo Municipal Hospital, 4005 Kamihongo, Matsudo 271-8511, Japan
Laboratory for Developmental Genetics, Riken Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
Department of Molecular Embryology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Department of Diabetes and Metabolic Disease, Asahi General Hospital, I-1136, Asahi 289-2511, Japan
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Department of Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
Translational Research Center, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Department of Internal Medicine, Social Insurance Funabashi Central Hospital, 6-13-10 Kaijin, Funabashi 273-8556, Japan
Department of Internal Medicine, Matsudo Municipal Hospital, 4005 Kamihongo, Matsudo 271-8511, Japan
Laboratory for Developmental Genetics, Riken Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
Department of Molecular Embryology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Department of Diabetes and Metabolic Disease, Asahi General Hospital, I-1136, Asahi 289-2511, Japan
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Department of Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
Translational Research Center, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Department of Internal Medicine, Social Insurance Funabashi Central Hospital, 6-13-10 Kaijin, Funabashi 273-8556, Japan
Department of Internal Medicine, Matsudo Municipal Hospital, 4005 Kamihongo, Matsudo 271-8511, Japan
Laboratory for Developmental Genetics, Riken Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
Department of Molecular Embryology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Department of Diabetes and Metabolic Disease, Asahi General Hospital, I-1136, Asahi 289-2511, Japan
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Department of Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
Translational Research Center, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Department of Internal Medicine, Social Insurance Funabashi Central Hospital, 6-13-10 Kaijin, Funabashi 273-8556, Japan
Department of Internal Medicine, Matsudo Municipal Hospital, 4005 Kamihongo, Matsudo 271-8511, Japan
Laboratory for Developmental Genetics, Riken Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
Department of Molecular Embryology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Department of Diabetes and Metabolic Disease, Asahi General Hospital, I-1136, Asahi 289-2511, Japan
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IRS-1 and IRS-2 may be regulated by factors other than insulin, including growth hormone, IGF-I, interferon-α and γ, prolactin, and cytokine signaling ( Argetsinger et al. 1995 , 1996 , Uddin et al. 1995 , Bole-Feysot et al. 1998 , Kulkarni
