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Tadamitsu Kishimoto

Publications and source records attributed to Tadamitsu Kishimoto.

At least 37 records · Page 2Linked to original sources
PubMed2004

SOCS-1 suppresses TNF-alpha-induced apoptosis through the regulation of Jak activation.

Suppressor of cytokine signaling-1 (SOCS-1) was identified as one of the negative feedback regulators of Janus kinase (Jak)-signal-transducer-and-activator-of-transcription (STAT) signaling. So far, it has been reported that SOCS-1 inhibits the action of multiple cytokines at least in vitro. We previously showed that SOCS-1 suppresses tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis in murine embryonic fibroblast, but the mechanism of suppression was not fully clarified. In this study, we show that Jaks bind to TNF receptor-1 (TNFR-1) and are activated by TNF-alpha. We also show that the activations of Jaks and caspases by TNF-alpha are suppressed by SOCS-1. Furthermore, in Jak-deficient cell lines, DNA fragmentation and caspase-8 activation by TNF-alpha are suppressed, indicating that Jaks participate in TNF-alpha-induced apoptosis signaling. Taken together, these results suggest that SOCS-1 inhibits TNF-alpha-induced apoptosis through regulation of Jaks.

Apoptosis↗
PubMed2004

Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial.

OBJECTIVE: Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL-6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL-6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti-IL-6 receptor antibody, MRA, in patients with RA. METHODS: In a multicenter, double-blind, placebo-controlled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria. RESULTS: Treatment with MRA reduced disease activity in a dose-dependent manner. At 3 months, 78% of patients in the 8-mg group, 57% in the 4-mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8-mg group versus placebo). Forty percent of patients in the 8-mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4-mg, and 8-mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti-DNA antibodies. Anti-MRA antibodies were detected in 2 patients. CONCLUSION: Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.

Adult↗
PubMed2004

Inhibition of IL-6 for the treatment of inflammatory diseases.

Interleukin-6 (IL-6) is a pleiotropic cytokine with various biological activities. Deregulated overproduction of IL-6 has been found to play pathological roles in chronic inflammatory diseases such as rheumatoid arthritis, Castleman's disease, juvenile idiopathic arthritis and Crohn's disease. Humanized anti-IL-6 receptor antibody has been developed as a therapeutic agent for these diseases, and therapeutic benefits have been revealed in clinical studies.

Animals↗
PubMed2004

TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling.

Alterations of TGF-beta signaling have been described in colorectal cancer, although the molecular consequences are largely unknown. By using transgenic mice overexpressing TGF-beta or a dominant-negative TGF-betaRII, we demonstrate that TGF-beta signaling in tumor infiltrating T lymphocytes controls the growth of dysplastic epithelial cells in experimental colorectal cancer, as determined by histology and a novel system for high-resolution chromoendoscopy. At the molecular level, TGF-beta signaling in T cells regulated STAT-3 activation in tumor cells via IL-6. IL-6 signaling required tumor cell-derived soluble IL-6R rather than membrane bound IL-6R and suppression of such TGF-beta-dependent IL-6 trans-signaling prevented tumor progression in vivo. Taken together, our data provide novel insights into TGF-beta signaling in colorectal cancer and suggest novel therapeutic approaches for colorectal cancer based on inhibition of TGF-beta-dependent IL-6 trans-signaling.

Animals↗
PubMed2004

A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease.

BACKGROUND & AIMS: Interleukin-6 (IL-6) regulates immune response and inflammation. We carried out a pilot placebo-controlled study to investigate the efficacy, pharmacokinetics, and safety of MRA, a humanized monoclonal antibody to IL-6 receptor, in patients with active Crohn's disease. METHODS: Thirty-six patients with active Crohn's disease (Crohn's Disease Activity Index [CDAI] > or =150) were randomly assigned to receive biweekly intravenous infusion of either placebo, MRA, or MRA/placebo alternately for 12 weeks at a dose of 8 mg/kg. The study's primary end point was a clinical response rate that was defined as a reduction of CDAI > or =70. RESULTS: At the final evaluation, 80% of the patients (8 of 10) given biweekly MRA had a clinical response as compared with 31% of the placebo-treated patients (4 of 13; P = 0.019). Twenty percent of the patients (2 of 10) on this regimen went into remission (CDAI <150), as compared with 0% of the placebo-treated patients (0 of 13). The clinical response rate of the every-4-week regimen was 42% (5 of 12). The serum concentrations of MRA were detected at 2 weeks after every infusion, at which time acute phase responses were completely suppressed; however, they were not suppressed at 4 weeks. Endoscopic and histologic examination showed no difference between MRA and placebo groups. The incidence of adverse events was similar in all the groups. CONCLUSIONS: This is the first clinical trial of humanized anti-IL-6 receptor monoclonal antibody in Crohn's disease. A biweekly 8 mg/kg infusion of MRA was well tolerated, normalized the acute-phase responses, and suggests a clinical effect in active Crohn's disease.

Adult↗
PubMed2004

Inadequate induction of suppressor of cytokine signaling-1 causes systemic autoimmune diseases.

Suppressor of cytokine signaling (SOCS)-1 is a cytokine-inducible, negative regulatory molecule of Janus kinases (JAK) and its deficiency causes hyper-response to various cytokines. SOCS-1(-/-) mice spontaneously develop a fatal disease depending on aberrantly activated lymphocytes. Here, we show that partial restoration of SOCS-1 in lymphoid cells rescues SOCS-1(-/-) mice from the early-onset fatal disease, indicating that SOCS-1 expression in vivo is especially required in lymphocytes. However, SOCS-1 expression in these SOCS-1-restored mutant mice (E( micro )-SOCS-1(-/-) mice) was insufficient for proper down-regulation of its target signaling, and these mice spontaneously exhibit hyperactivation of lymphocytes, an increase in the levels of serum Ig and anti-DNA autoantibodies, and glomerulonephritis with glomerular IgG deposition. These phenotypes resemble those of murine systemic autoimmune diseases, models for systemic lupus erythematosus (SLE). Interestingly, similar phenotypes were also observed in adult female SOCS-1(+/-) mice, indicating that the autoimmune phenotypes of these mice can be ascribed primarily to the inadequate expression of SOCS-1. In addition, autoimmune phenotypes were not observed in SOCS-1(+/-)CD4(-/-) mice, suggesting that autoimmunity is dependent on hyper-activated CD4(+) T cells. Our findings also suggest that insufficient expression of SOCS-1 results in impaired function of CD25(+)CD4(+) regulatory T cells, which may contribute to aberrant activation of CD4(+) T cells. These findings suggest that dysfunction of SOCS-1 can be a pathogenic factor of systemic autoimmune diseases such as SLE.

Animals↗
PubMed2004

Hypermethylation-associated inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in human pancreatic cancers.

BACKGROUND: SOCS-1, a JAK-binding protein (SSI-1/SOCS-1/JAB), regulates the JAK/STAT signal transduction pathway that relays signals from various cytokines in the extracellular matrix into the cell. Inactivation of the SOCS-1 gene by methylation has been previously described in hepatocellular carcinomas and multiple myeloma. The purpose of the present work was to analyze the expression of the SOCS-1 gene and identify inactivation of this gene by methylation in pancreatic cancers. METHODS: 20 samples were analyzed. We identified the expression of SOCS-1 gene using RT-PCR and the mechanism of inactivation in this gene by methylation assay. RESULTS: We documented marked suppression of SOCS-1 mRNA and reduction of SOCS-1 protein in 7 of 14 primary pancreatic cancers examined; moreover, CpG-rich regions upstream of the SOCS-1 gene were hypermethylated in 8 of the 14 tumors. CONCLUSIONS: The results suggested that this gene is silenced in a substantial portion of pancreatic cancers through mechanisms that cause methylation in the promoter region.

Aged↗
PubMed2004

Suppressor of cytokine signalling-1 gene silencing in acute myeloid leukaemia and human haematopoietic cell lines.

The aim of this study was to investigate whether the suppressor of cytokine signalling (SOCS)-1 can act as a tumour suppressor when functioning as a negative regulator of the Janus family tyrosine kinases (JAKs), which have been reported to play important roles in leukaemogenesis. For this purpose, we carried out molecular analysis of the SOCS-1 gene in human acute myeloid leukaemia (AML) and human haematopoietic cell lines. Sequencing alterations in the coding region were found in two of 90 primary AML samples and one of 17 cell lines. Hypermethylation of the SOCS-1 gene was also observed in 72% of primary cases and 52% of cell lines and aberrant methylation strongly correlated with reduced expression. Transfection of SOCS-1 into Jurkat cells harbouring the mutation and methylation suppressed cell growth at a low serum concentration. These findings indicate that SOCS-1 is frequently silenced in haematopoietic malignancies, mainly as a result of hypermethylation, and suggest that SOCS-1 may be able to function as a tumour suppressor.

Acute Disease↗
PubMed2004

Humanized anti-interleukin 6 receptor antibody induced long-term remission in a patient with life-threatening refractory autoimmune hemolytic anemia.

Refractory autoimmune hemolytic anemia (AIHA) is associated with considerable rates of mortality. Interleukin 6 (IL-6) has been reported to play a role in the pathogenesis of AIHA. This report describes a patient with AIHA who was successfully treated with a humanized anti-human IL-6 receptor (IL-6R) monoclonal antibody (MoAb). He had experienced life-threatening AIHA and had received conventional therapy with corticosteroids, azathioprine, cyclophosphamide, cyclosporin A, melphalan, plasma exchange, and irradiation to his spleen. However, the patient's symptoms and laboratory data did not show a sufficient improvement. Because his serum IL-6 level was elevated, we attempted to block IL-6 signaling by using a humanized anti-IL-6R MoAb, MRA. With 8 mg/kg of MRA administration every 2 weeks, the serum hemoglobin level gradually increased and normalized within 4 months. After 2 years of MRA treatment, the disease activity was well controlled without adverse reactions. Anti-IL-6R MoAb can be a novel and effective therapeutic agent for AIHA.

Adult↗
PubMed2004

Anti-interleukin 6 receptor antibody inhibits murine AA-amyloidosis.

OBJECTIVE: AA-amyloidosis is a severe complication in chronic inflammatory diseases. AA-amyloidosis is caused by the deposition of insoluble fibrils containing AA amyloid protein derived from serum amyloid A (SAA), which is synthesized by inflammatory cytokine stimulation. We examined whether anti-interleukin 6 receptor (IL-6R) antibody prevented the development of AA-amyloidosis in mouse models. METHODS: A transient model was induced by the injection of amyloid enhancing factor (AEF) and adjuvant treatment in C57BL/6 mice. Monoclonal IgG1 antibody, MR16-1, was injected intraperitoneally just once before the injection of AEF and adjuvant. After 2 and 5 weeks, mice were sacrificed and histologically examined. In contrast, a chronic model was induced by AEF injection into IL-6 transgenic mice. One week later, in order to avoid neutralizing antibody production, MR16-1 (200 mg/kg) was injected intravenously. MR16-1 (5 mg/kg) was injected subcutaneously twice a week from the next week. Three and 6 weeks after AEF injection, mice were sacrificed and histologically examined. RESULTS: In the transient model, amyloid deposition was observed in the spleen, liver, and kidney as early as 2 weeks after treatment. MR16-1 completely prevented amyloid deposition. Although IL-6 production was not suppressed, SAA production was significantly suppressed. In the chronic model, substantial amyloid deposition was seen in multiple organs and tissues as well as the spleen, liver, and kidney. MR16-1 suppressed amyloid deposition in many organs, even when injected one week after AEF injection; it showed a tendency to decrease SAA and IL-6 levels were decreased. CONCLUSION: IL-6 is a key cytokine for the induction of AA-amyloidosis, and anti-IL-6R therapy appears promising for the treatment of AA-amyloidosis.

Amyloidosis↗
PubMed2003

Impaired colonization of the gonads by primordial germ cells in mice lacking a chemokine, stromal cell-derived factor-1 (SDF-1).

Primordial germ cells (PGCs) are the founders of sperm or oocytes. PGCs migrate through the tissues of the embryos and colonize the gonads during development. However, the cytokines essential for colonization of the gonads by PGCs in mammals remain unclear. Stromal cell-derived factor-1 (SDF-1, also called PBSF and CXCL12) is a member of chemokines, a family of structurally related chemoattractive cytokines. SDF-1 and its primary physiologic receptor CXCR4 have multiple essential functions in development including colonization of bone marrow by hematopoietic cells and neuron localization within cerebellum during embryogenesis as well as B lymphopoiesis and cardiovasculogenesis. Here, we have shown that PGCs have cell-surface expression of CXCR4 and that, in SDF-1(-/-) mice, PGCs undergo directed migration through tissues of embryos, but the numbers of PGCs in the gonads are significantly reduced. The proliferation of PGCs within the gonads seems normal in the mutant mice. These findings reveal the essential role for SDF-1 in murine PGC development likely by controlling colonization of the gonads by PGCs.

Animals↗
PubMed2003

Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis.

OBJECTIVE: To investigate whether interleukin-6 (IL-6) is a regulator of vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA). METHODS: Serum VEGF levels in RA patients were assayed before and after 8 weeks or 24 weeks of maintenance therapy with humanized anti-IL-6 receptor monoclonal antibody (anti-IL-6R mAb). VEGF secreted by RA synovial fibroblasts cultured in the presence of IL-6, IL-1beta, and/or tumor necrosis factor alpha (TNFalpha) was measured. The inhibitory effect of anti-IL-6R mAb, recombinant IL-1 receptor antagonist (IL-1Ra), and anti-TNFalpha mAb on VEGF production was also examined. RESULTS: Serum VEGF levels in RA patients before anti-IL-6R mAb therapy were significantly higher than those in healthy controls (P < 0.0005). Treatment of RA patients with anti-IL-6R mAb normalized serum VEGF levels. In the in vitro study, IL-6 and IL-1beta each induced a slight amount of VEGF production in synovial cells, but TNFalpha did not. Although VEGF-inducing activity of these cytokines was not remarkable when they were added alone, IL-6 acted synergistically with IL-1beta or TNFalpha to induce VEGF production. There was no synergistic effect between IL-1beta and TNFalpha. In the presence of all of these cytokines, anti-IL-6R mAb eliminated the synergistic effect of IL-6, IL-1beta, and TNFalpha, while IL-1Ra or anti-TNFalpha mAb did not. CONCLUSION: Anti-IL-6R mAb therapy reduced VEGF production in RA. IL-6 is the pivotal cytokine that induces VEGF production in synergy with IL-1beta or TNFalpha, and this may be the mechanism by which IL-6 blockade effectively suppresses VEGF production in synovial fibroblasts.

Antibodies, Monoclonal↗
PubMed2003

Hypermethylation associated with inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in human hepatoblastomas.

We recently demonstrated inactivation in hepatocellular carcinomas (HCCs) of the gene encoding SOCS1/JAB1/SSI-1, a JAK-binding protein that regulates the JAK/STAT signal-transduction pathway. In a follow-up immunochemical investigation of expression of SOCS-1 in hepatoblastomas (HBLs), the protein was markedly reduced in half of the HBL tumors we examined. CpG-rich regions upstream of the SOCS-1 gene were hypermehylated in 7 of the 15 HBL cases. The results suggest that hypermethylation may play an important role in silencing the SOCS-1 gene, not only in adult HCCs, but also in liver tumors arising in childhood.

Adolescent↗
PubMed2003

Synergistic effect on the attenuation of collagen induced arthritis in tumor necrosis factor receptor I (TNFRI) and interleukin 6 double knockout mice.

OBJECTIVE: To evaluate any additive effect on attenuation of collagen induced arthritis (CIA) in tumor necrosis factor receptor I (TNFRI) and interleukin 6 (IL-6) double knockout (DKO) mice. METHODS: CIA was induced in wild-type (Wt), TNFRI knockout (TNFRIKO), IL-6 knockout (IL-6KO), and DKO mice. Comparative studies were performed among these different mouse genotypes observing clinical (incidence, arthritis score), histological, radiologic, and immunological aspects. RESULTS: More than 90% of the Wt, TNFRIKO, and IL-6KO mice developed definite CIA, while only 20% of the DKO mice did so. Severity of arthritis, indicated by the arthritis score, was significantly reduced in both the TNFRIKO and IL-6KO mice compared with the Wt mice. Moreover, the severity of arthritis in the DKO mice was significantly reduced compared with each single KO mouse (by arthritis scores; DKO vs TNFRIKO, IL-6KO mice, p < 0.05). In addition, histological and radiologic changes were also significantly reduced in the DKO mice compared with each single KO mouse (by histological and radiologic scores; DKO vs TNFRIKO, IL-6KO mice, p < 0.05 and p < 0.01 respectively). In immunological studies, serum anti-type II collagen (anti-CII) antibody concentrations were significantly decreased in the DKO mice compared with each single KO mouse (DKO vs TNFRIKO, IL-6KO mice, p < 0.01). CONCLUSION: Simultaneous blockade of TNFRI and IL-6 showed synergistic rather than additive effects on the attenuation of CIA. Combinations of anti-TNF-a and anti-IL-6 therapy may provide clinical benefits for treatment of rheumatoid arthritis compared with therapy against each single cytokine.

Animals↗
PubMed2003

Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study.

OBJECTIVE: To evaluate the safety and pharmacokinetics of multiple infusions of a humanized anti-interleukin-6 (IL-6) receptor antibody, MRA, in patients with rheumatoid arthritis (RA). METHODS: In an open label trial, 15 patients with active RA were intravenously administered 3 doses (2, 4, or 8 mg/kg) of MRA biweekly for 6 weeks, and pharmacokinetics were assessed. Patients continued on MRA treatment for 24 weeks, and were then assessed for safety and efficacy. RESULTS: The treatment was well tolerated at all doses with no severe adverse event. Increased total serum cholesterol was detected as an MRA related reaction in 10/15 (66%) patients. There was no statistically significant difference in the frequency of adverse events among the 3 dose groups. There were no new observations of antinuclear antibody or anti-DNA antibody, and no anti-MRA antibody was detected. The T1/2 increased with repeated doses and as the dose increased. T1/2 after the 3rd dose of 8 mg/kg reached 241.8 +/- 71.4 h. In 12/15 (80%) patients whose serum MRA was detectable during the treatment period, objective inflammatory indicators such as C-reactive protein, erythrocyte sedimentation rate, and serum amyloid A were completely normalized at 6 weeks, although there was no statistically significant difference in efficacy among the 3 dose groups. Nine of 15 patients achieved ACR 20 at 6 weeks. At 24 weeks, 13 patients achieved ACR 20 and 5 achieved ACR 50. CONCLUSION: Repetitive treatment with MRA was safe and normalized acute phase response in patients with RA. Optimal dosing schedule was not defined in this small study, but maintenance of serum MRA concentration seemed important to achieve efficacy.

Acute-Phase Reaction↗
PubMed2002

Anti-interleukin 6 (IL-6) receptor antibody suppresses Castleman's disease like symptoms emerged in IL-6 transgenic mice.

Transgenic mice carrying human IL-6 cDNA fused with a murine major histocompatibility class-I promoter (H-2L(d)) were serially administered with anti-interleukin-6 receptor (IL-6R) monoclonal antibody (mAb), MR16-1, from the age of 4 weeks to estimate its efficacy on a variety of disorders developed in these mice, most of which are similar to the disorders associated with Castleman's disease. In the control mice treated with isotype-matched mAb, a massive and multiple IgG1 plasmacytosis, mesangial proliferative glomerulonephritis, leukocytosis, thrombocytosis, anemia and abnormalities of blood chemical parameters have developed in accordance with the elevation of serum IL-6, and 50% of mice have died of renal failure by 18 weeks of age. In contrast, the treatment with MR16-1 prevented all these symptoms and prolonged the lifetime of the majority of the mice. Thus, the constitutive overexpression of IL-6 caused various disorders, and the treatment with anti-IL-6R mAb completely prevented from these symptoms. These results clearly confirm that IL-6 indeed plays an essential role in the pathogenesis of a variety of disorders. Furthermore, anti-IL-6R mAb could provide novel therapy for Castleman's disease and MR16-1 should be a useful tool to estimate therapeutic potential of IL-6 antagonists in a variety of murine models for human disease.

Animals↗
PubMed2002

Expression of the suppressor of cytokine signaling-5 (SOCS5) negatively regulates IL-4-dependent STAT6 activation and Th2 differentiation.

The development of helper T (Th) cell subsets, which secrete distinct cytokines, plays an important role in determining the type of immune response. The IL-4-mediated Janus kinase-signal transducer and activator of transcription signaling pathway is crucial for mediating Th2 cell development. Notably, this pathway is selectively impaired in Th1 cells, although the molecular basis of this impairment remains unclear. We show here that during Th1 differentiation a reduction in the association of Janus kinase 1 with the IL-4 receptor (IL-4R) correlated with the appearance of the suppressor of cytokine signaling-5 (SOCS5). SOCS5 protein was preferentially expressed in committed Th1 cells and interacted with the cytoplasmic region of the IL-4Ralpha chain irrespective of receptor tyrosine phosphorylation. This unconventional interaction of SOCS5 protein with the IL-4R resulted in the inhibition of IL-4-mediated signal transducer and activator of transcription-6 activation. T cells from transgenic mice constitutively expressing SOCS5 exhibited a significant reduction of IL-4-mediated Th2 development. Therefore, the induced SOCS5 protein in Th1 differentiation environment may play an important role by regulating Th1 and Th2 balance.

Animals↗