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Immunoregulatory Cytokine (immunoregulatory + cytokine)
Selected AbstractsA multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis,,HEPATOLOGY, Issue 3 2010Silvia Ferri Immunotolerance is maintained by regulatory T cells (Tregs), including CD4+CD25hi, CD8+CD28,, ,,, and CD3+CD56+ [natural killer T (NKT)] cells. CD4+CD25hi cells are impaired in children with autoimmune hepatitis (AIH). Little is known about Tregs in adults with AIH. The aim of this study was to investigate the frequency and function of Treg subsets in adult patients with AIH during periods of active disease and remission. Forty-seven AIH patients (16 with active disease and 31 in remission) and 28 healthy controls were studied. Flow cytometry was used to evaluate surface markers and function-related intracellular molecules in ,,, CD8+CD28,, NKT, and CD4+CD25hi cells. CD4+CD25hi T cell function was determined by the ability to suppress proliferation and interferon gamma (IFN-,) production by CD4+CD25, target cells. Liver forkhead box P3,positive (FOXP3+) cells were sought by immunohistochemistry. In AIH patients, particularly during active disease, CD4+CD25hi T cells were fewer, expressed lower levels of FOXP3, and were less effective at inhibiting target cell proliferation versus healthy controls. Moreover, although the numbers of CD8+CD28, T cells were similar in AIH patients and healthy controls, NKT cells were numerically reduced, especially during active disease, and produced lower quantities of the immunoregulatory cytokine interleukin-4 versus controls. In contrast, ,, T cells in AIH patients were more numerous versus healthy controls and had an inverted V,1/V,2 ratio and higher IFN-, and granzyme B production; the latter was correlated to biochemical indices of liver damage. There were few FOXP3+ cells within the portal tract inflammatory infiltrate. Conclusion: Our data show that the defect in immunoregulation in adult AIH is complex, and ,, T cells are likely to be effectors of liver damage. (HEPATOLOGY 2010) [source] Clinical importance of serum interleukin-18 and nitric oxide activities in breast carcinoma patientsCANCER, Issue 3 2002Nazan Günel M.D. Abstract BACKGROUND Interleukin-18 (IL-18) is a novel immunoregulatory cytokine that was known previously as interferon-,,inducing factor. IL-18 levels can be used as a serum indicator for monitoring the clinical course of patients with hematologic malignancies and gastric carcinoma. Nitric oxide (NO) is a pleiotropic molecule that participates in the multistep processing of carcinogenesis. METHODS In the current study, we measured serum IL-18 and nitrate and nitrite levels in 38 metastatic and 26 nonmetastatic breast carcinoma patients and 16 healthy control subjects. Serum nitrate and nitrite levels were measured as an index of NO generation. RESULTS The levels of serum IL-18 and nitrate and nitrite were increased significantly in breast carcinoma patients compared with control subjects (P < 0.001). Serum IL-18 levels were significantly higher in the metastatic patients compared with the nonmetastatic patients (P < 0.001). There was no difference in serum nitrate and nitrite levels between metastatic and nonmetastatic patients (P > 0.05). Patients with bone metastasis have higher serum IL-18 levels and lower serum nitrate and nitrite levels compared with patients with liver, lung, and local metastasis (P < 0.001). There was no correlation among serum IL-18, nitrate and nitrite, CA 15-3, and carcinoemybryonic antigen levels (P > 0.05). CONCLUSIONS These findings suggest that serum IL-18 and nitrate and nitrite levels may be useful markers in monitoring metastatic breast carcinoma pateints. IL-18 and NO activities in breast carcinoma patients with bone metastasis may be more valuable in the follow-up of these patients. Cancer 2002;95:663,7. © 2002 American Cancer Society. DOI 10.1002/cncr.10705 [source] Calcineurin deficiency decreases inflammatory lesions in transforming growth factor ,1-deficient miceCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2009R. Bommireddy Summary Transforming growth factor (TGF) ,1) is an immunoregulatory cytokine involved in self-tolerance and lymphocyte homeostasis. Tgfb1 knock-out (KO) mice develop severe multi-focal autoimmune inflammatory lesions due to [Ca2+]i deregulation in T cells, and die within 3 weeks after birth. Because the calcineurin inhibitor FK506 inhibits the hyperresponsiveness of Tgfb1,/, thymocytes, and because calcineurin A, (CNA,)-deficient mice do not reject allogenic tumours, we have generated Tgfb1,/,Cnab,/, mice to address whether CNA, deficiency prevents T cell activation and inflammation in Tgfb1,/, mice. Here we show that in Tgfb1,/,Cnab,/, mice inflammation is reduced significantly relative to that in Tgfb1,/, mice. However, both CD4+ and CD8+ T cells in double knock-out (DKO) mice are activated, as revealed by up-regulation of CD11a lymphocyte function-associated antigen-1 (LFA-1), CD44 and CD69 and down-regulation of CD62L. These data suggest that deficiency of CNA, decreases inflammatory lesions but does not prevent activation of autoreactive T cells. Also Tgfb1,/, T cells can undergo activation in the absence of CNA,, probably by using the other isoform of calcineurin (CNA,) in a compensatory manner. CNA,-deficient T cells undergo spontaneous activation in vivo and are activated upon anti-T cell receptor stimulation in vitro. Understanding the role of calcineurin in T cell regulation should open up new therapeutic opportunities for inflammation and cancer. [source] Inhibition of p38 MAP kinase during cellular activation results in IFN-,-dependent augmentation of IL-12 production by human monocytes/macrophagesCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 1 2001J. B. Marriott Interleukin-12 (IL-12) is a key immunomodulatory cytokine produced by antigen-presenting cells that promotes cellular immunity and enables the generation of protective immunity against intracellular pathogens and tumours. Therefore, modulation of IL-12 activity is a primary immunotherapeutic goal. However, little is known about its regulation. Signalling via p38 MAPK has been implicated in the control of inflammatory responses and is therefore a potential therapeutic target. We have used the highly selective p38 MAPK inhibitor (SB203580) to examine the effect of this pathway on the production of IL-12. Surprisingly, we found that SB203580 strongly up-regulated LPS induced IL-12p40 at the protein (intracellular and secreted) and mRNA levels in PBMC cultures. The effect on IL-12 was apparent using both T cell-independent and T cell-dependent stimuli but not in unstimulated cultures, indicating that activation signals are required. Furthermore, the production of IFN- , by T cells is crucial as production was not increased in LPS-stimulated, purified adherent monocytes/macrophages without the addition of exogenous IFN- ,. These results provide evidence that p38 MAPK has an unexpected suppressive effect on IL-12p40 gene transcription, and suggests interplay between p38 MAPK- and IFN- , -mediated signals in the regulation of IL-12 production by monocytes/macrophages. Furthermore, the importance of IL-12 as a key immunoregulatory cytokine suggests that the clinical application of pyrinidyl imidazole inhibitors, such as SB203580, may need to be reassessed. [source] Effect of pro-inflammatory and immunoregulatory cytokines on human tenocytesJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 8 2010Thilo John Abstract Tendon injury induces a local inflammatory response, characterized by the induction of pro-inflammatory cytokines. The aim of the present study was to analyze the effects of TNF,, IL-6 and IL-10 on key parameters of tendon homeostasis. Cultured primary human tenocytes were treated with the recombinant cytokines IL-6, IL-10, TNF,, or combinations of TNF, with IL-6 and IL-10 (10 ng/mL, 6, 24 h). Expression of type I collagen, elastin, MMP-1, TNF,, IL-1,, IL-6, IL-10, and suppressors of cytokine signaling (SOCS1, 3) was analyzed with the use of RTD-PCR, immunocytochemistry, and Western blot analysis. In response to TNF,, tenocytes reduced their type I collagen deposition but increased their elastin gene expression and highly upregulated their expression for MMP-1, pro-inflammatory (TNF,, IL-1,) and immunoregulatory (IL-6, IL-10) cytokines. TNF, stimulation augmented SOCS1, whereas SOCS3 expression in tenocytes was also induced by IL-6. The treatment of tenocytes with IL-6 and IL-10 had no effect on cytokine expression. Neither IL-6 nor IL-10 modulated the observed effects of TNF, significantly. These results indicate that TNF, strongly activates the tenocytes to amplify their own TNF, expression and, subsequently, that of other regulatory cytokines and matrix degrading enzymes. However, the impact of IL-6 and IL-10 on tenocytes remains unclear. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1071,1077, 2010 [source] Grape seed proanthocyanidines and skin cancer prevention: Inhibition of oxidative stress and protection of immune systemMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue S1 2008Santosh K. Katiyar Abstract Overexposure of the skin to UV radiation has a variety of adverse effects on human health, including the development of skin cancers. There is a need to develop nutrition-based efficient chemopreventive strategies. The proanthocyanidins present in grape seeds (Vitis vinifera) have been shown to have some biological effects, including prevention of photocarcinogenesis. The present communication discusses the in vitro and in vivo studies of the possible protective effect of grape seed proanthocyanidins (GSPs) and the molecular mechanism for these effects. In SKH-1 hairless mice, dietary supplementation with GSPs is associated with a decrease of UVB-induced skin tumor development in terms of tumor incidence, tumor multiplicity, and a decrease in the malignant transformation of papillomas to carcinomas. It is suggested that the chemopreventive effects of dietary GSPs are mediated through the attenuation of UV-induced: (i) oxidative stress; (ii) activation of mitogen-activated protein kinases and nuclear factor-kappa B (NF-,B) signaling pathways; and (iii) immunosuppression through alterations in immunoregulatory cytokines. Collectively, these studies indicate protective potential of GSPs against experimental photocarcinogenesis in SKH-1 hairless mice, and the possible mechanisms of action of GSPs, and suggest that dietary GSPs could be useful in the attenuation of the adverse UV-induced health effects in human skin. [source] REVIEW ARTICLE: Th1/Th2/Th17 and Regulatory T-Cell Paradigm in PregnancyAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2010Shigeru Saito Citation Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am J Reprod Immunol 2010 T-helper (Th) cells play a central role in modulating immune responses. The Th1/Th2 paradigm has now developed into the new Th1/Th2/Th17 paradigm. In addition to effector cells, Th cells are regulated by regulatory T (Treg) cells. Their capacity to produce cytokines is suppressed by immunoregulatory cytokines such as transforming growth factor (TGF)-, and interleukin (IL)-10 or by cell-to-cell interaction. Here, we will review the immunological environment in normal pregnancy and complicated pregnancy, such as implantation failure, abortion, preterm labor, and preeclampsia from the viewpoint of the new Th1/Th2/Th17 and Treg paradigms. [source] Ex vivo Inhibition of NF-,B Signaling in Alloreactive T-cells Prevents Graft-Versus-Host DiseaseAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2009M. J. O'Shaughnessy The ex vivo induction of alloantigen-specific hyporesponsiveness by costimulatory pathway blockade or exposure to immunoregulatory cytokines has been shown to inhibit proliferation, IL-2 production, and the graft-versus-host disease (GVHD) capacity of adoptively transferred T-cells. We hypothesized that inhibition of the intracellular NF-,B pathway in alloreactive T-cells, which is critical for T-cell activation events including IL-2 transcription, could lead to alloantigen hyporesponsiveness and loss of GVHD capacity. We demonstrate that treatment of mixed lymphocyte reaction (MLR) cultures with PS1145, a potent inhibitor of NF-,B activation, can induce T-cell hyporesponsiveness to alloantigen in primary and secondary responses while preserving in vitro responses to potent mitogenic stimulation. GVHD lethality in recipients of ex vivo PS1145-treated cells was profoundly inhibited. Parking of control or PS1145-treated MLR cells in syngeneic Rag,/, recipients resulted in intact contact hypersensitivity (CHS) responses. However, GVHD lethality capacity also was restored, suggesting that lymphopenic expansion uncoupled alloantigen hyporesponsiveness. These results indicate that the NF-,B pathway is a critical regulator of alloresponses and provide a novel small molecule inhibitor based approach that is effective in preventing early posttransplant GVHD lethality but that also permits donor T-cell responses to recover after a period of lymphopenic expansion. [source] | |||||||||||||