scholarly journals Suppressor of cytokine signaling gene expression in human pancreatic islets: modulation by cytokines

2005 ◽  
Vol 152 (3) ◽  
pp. 485-489 ◽  
Author(s):  
Carmela Santangelo ◽  
Angela Scipioni ◽  
Lorella Marselli ◽  
Piero Marchetti ◽  
Francesco Dotta
Keyword(s):  
Pancreatic Islets ◽  
Inflammatory Process ◽  
Human Islets ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Human Pancreatic Islets ◽  
Tnf Α ◽  
Ifn Γ

Objective: Suppressor of cytokine signaling (SOCS) proteins negatively regulate signal transduction of several cytokines. Since cytokines participate in the pancreatic islet damage in type 1 diabetes, the aim of our study was to investigate the expression of SOCS-1, -2 and -3 in isolated human islets, in basal conditions and after exposure, in vitro, to a combination of interferon (IFN)-γ, interleukin (IL)-1β and tumor necrosis factor (TNF)-α cytokines and in control and in type 1 diabetic human pancreata, to establish (i) whether SOCS molecules are constitutively expressed in human pancreatic islets and (ii) whether their expression can be modulated in vitro by proinflammatory cytokines or ex vivo by an islet inflammatory process. Methods: Gene expression of SOCS-1, -2 and -3 was evaluated by RT-PCR in untreated and cytokine-treated isolated human pancreatic islets and their protein expression by immunohistochemistry in control and in type 1 diabetic human pancreata paraffin-embedded sections. Results: We found that SOCS-1, -2 and -3 mRNA is constitutively, although weakly, expressed in human pancreatic islets, similar to the expression observed in control pancreata by immunohistochemistry. SOCS-1, -2 and -3 mRNA expression was strongly increased in human islets after exposure, in vitro, to IFN-γ, IL-1β and TNF-α. Accordingly, an intense and islet-specific immunohistochemical staining for all three SOCS was detected in pancreata from type 1 diabetic patients. Conclusion: SOCS-1, -2 and -3 genes are constitutively expressed in human pancreatic islets; their expression increases after exposure to proinflammatory cytokines and during an autoimmune inflammatory process, raising the possibility that these molecules act as key regulators of cytokine signaling in pancreatic islets.

scholarly journals Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jatin Sharma ◽  
Teresa D. Collins ◽  
Tracoyia Roach ◽  
Shiwangi Mishra ◽  
Brandon K. Lam ◽  
...  
Keyword(s):  
Intraperitoneal Administration ◽  
Lymphocyte Activation ◽  
Signal Propagation ◽  
Skin Lesions ◽  
Effector Memory ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Autoantibody Production ◽  
Ifn Γ

AbstractAutoimmune diseases are driven largely by a pathogenic cytokine milieu produced by aberrantly activated lymphocytes. Many cytokines, including interferon gamma (IFN-γ), utilize the JAK/STAT pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS1) is an inducible, intracellular protein that regulates IFN-γ signaling by dampening JAK/STAT signaling. Using Fas deficient, MRL/MpJ-Faslpr/J (MRL/lpr) mice, which develop lupus-like disease spontaneously, we tested the hypothesis that a peptide mimic of the SOCS1 kinase inhibitory region (SOCS1-KIR) would inhibit lymphocyte activation and modulate lupus-associated pathologies. Consistent with in vitro studies, SOCS1-KIR intraperitoneal administration reduced the frequency, activation, and cytokine production of memory CD8+ and CD4+ T lymphocytes within the peripheral blood, spleen, and lymph nodes. In addition, SOCS1-KIR administration reduced lymphadenopathy, severity of skin lesions, autoantibody production, and modestly reduced kidney pathology. On a cellular level, peritoneal SOCS1-KIR administration enhanced Foxp3 expression in total splenic and follicular regulatory T cells, reduced the effector memory/naïve T lymphocyte ratio for both CD4+ and CD8+ cells, and reduced the frequency of GL7+ germinal center enriched B cells. Together, these data show that SOCS1-KIR treatment reduced auto-reactive lymphocyte effector functions and suggest that therapeutic targeting of the SOCS1 pathway through peptide administration may have efficacy in mitigating autoimmune pathologies.

scholarly journals Distinct mechanisms of induction of hepatic growth hormone resistance by endogenous IL-6, TNF-α, and IL-1β

2014 ◽  
Vol 307 (2) ◽  
pp. E186-E198 ◽  
Author(s):  
Yueshui Zhao ◽  
Xiaoqiu Xiao ◽  
Stuart J. Frank ◽  
Herbert Y. Lin ◽  
Yin Xia
Keyword(s):  
Growth Hormone ◽  
Target Gene ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Gh Receptor ◽  
Tnf Α ◽  
Igf I ◽  
Socs3 Expression ◽  
Gh Resistance

During inflammation, the liver becomes resistant to growth hormone (GH) actions, leading to downregulation of the GH target gene IGF-I and activation of catabolism. Proinflammatory cytokines IL-6, TNF-α, and IL-1β are critically involved in the pathogenesis of hepatic GH resistance. However, the mechanisms used by endogenous IL-6, TNF-α, and IL-1β to inhibit the hepatic GH-IGF-I pathway during inflammation are not fully understood. Here, we show that TNF-α and IL-1β inhibited GH receptor (GHR) expression but had minor effects on the downstream suppressor of cytokine signaling (SOCS)3, while IL-6 induced SOCS3 expression but had no effect on GHR expression in Huh-7 cells. Consistent with the in vitro observations, neutralization of TNF-α and IL-1β in mouse models of inflammation did not significantly alter SOCS3 expression stimulated by inflammation but restored GHR and IGF-I expression suppressed by inflammation. Neutralization of IL-6 did not alter inflammation-suppressed GHR expression but drastically reduced the inflammation-stimulated SOCS3 expression and restored IGF-I expression. Interestingly, when the GH-IGF-I pathway was turned off by maximal inhibition of GHR expression, IL-6 and SOCS3 were no longer able to regulate IGF-I expression. Taken together, our results suggest that TNF-α/IL-1β and IL-6 use distinct mechanisms to induce hepatic GH resistance, with TNF-α and IL-1β acting primarily on GHR and IL-6 acting primarily on SOCS3. IL-6 action may be superseded by factors such as TNF-α and IL-1β that inhibit GHR expression.

scholarly journals Differential Regulation of DAP12 and Molecules Associated with DAP12 during Host Responses to Mycobacterial Infection

2004 ◽  
Vol 72 (5) ◽  
pp. 2477-2483 ◽  
Author(s):  
Naoko Aoki ◽  
Anna Zganiacz ◽  
Peter Margetts ◽  
Zhou Xing
Keyword(s):  
Mycobacterial Infection ◽  
Host Responses ◽  
Necrosis Factor Alpha ◽  
Lung Macrophage ◽  
Tnf Α ◽  
Kinetic Expression ◽  
Ifn Γ

ABSTRACT DAP12 and its associating molecules MDL-1, TREM-1, and TREM-2 are the recently identified immune regulatory molecules, expressed primarily on myeloid cells including monocytes/macrophages, dendritic cells, NK cells, and neutrophils. However, little is known about the regulation of their expression during host antimicrobial responses. We have investigated the effect of pulmonary mycobacterial infection and type 1 cytokines on the expression of these molecules both in vivo and in vitro. While DAP12 was constitutively expressed at high levels in the lungs, the MDL-1, TREM-1, and TREM-2 molecules were inducible during mycobacterial infection. Their kinetic expression was correlated with that of the type 1 cytokines tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ). In primary lung macrophage cultures, high constitutive levels of DAP12 and TREM-2 were not modulated by mycobacterial or type 1 cytokine exposure. In contrast, expression of both MDL-1 and TREM-1 was markedly induced by mycobacterial infection and such induction was inhibited by concurrent exposure to IFN-γ. On mycobacterial infection of TNF-α−/− and IFN-γ−/− mice in vivo or their lung macrophages in vitro, TNF-α was found to be critical for mycobacterially induced MDL-1, but not TREM-1, expression whereas IFN-γ negatively regulated mycobacterially induced MDL-1 and TREM-1 expression. Our findings thus suggest that DAP12 and its associating molecules are differentially regulated by mycobacterial infection and type 1 cytokines and that MDL-1- and TREM-1-triggered DAP12 signaling may play an important role in antimicrobial type 1 immunity.

scholarly journals Type 1 Chemokine Receptor Expression in Chagas' Disease Correlates with Morbidity in Cardiac Patients

2005 ◽  
Vol 73 (12) ◽  
pp. 7960-7966 ◽  
Author(s):  
Juliana A. S. Gomes ◽  
Lilian M. G. Bahia-Oliveira ◽  
Manoel Otávio C. Rocha ◽  
Solange C. U. Busek ◽  
Mauro M. Teixeira ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Significant Positive Correlation ◽  
Receptor Expression ◽  
Necrosis Factor Alpha ◽  
Positive Correlation ◽  
Intracellular Cytokines ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT Chemokines and chemokine receptors (CKRs) control the migration of leukocytes during the inflammatory process and are important immunological markers of type 1 (CCR5 and CXCR3) and type 2 (CCR3 and CCR4) responses. The coexpression of CKRs (CCR2, CCR3, CCR5, CXCR3, and CXCR4) and intracellular cytokines (interleukin-10 [IL-10], IL-4, tumor necrosis factor alpha [TNF-α], and gamma interferon [IFN-γ]) on T CD4+ and CD8+ peripheral cells from individuals with indeterminate (IND) or cardiac (CARD) clinical forms of Chagas' disease after in vitro stimulation with Trypanosoma cruzi antigens, were evaluated in this study. The percentage of T CD4+ and CD8+ cells coexpressing CCR5 and IFN-γ, CXCR3 and IFN-γ, and CXCR3 and TNF-α were higher in CARD than in IND individuals; on the other hand, the percentage of T CD4+ or CD8+ cells coexpressing CCR3 and IL-10 or coexpressing CCR3 and IL-4 were lower in CARD individuals than in IND individuals. In addition, a significant positive correlation between the expression of CCR5 or CXCR3 and IFN-γ was observed in CARD individuals contrasting with a significant positive correlation between the expression of CCR3 and IL-4 and of CCR3 and IL-10 in IND patients. These results reinforce the hypothesis that a T. cruzi-exacerbated specific type 1 immune response developed by CARD chagasic patients is associated with the development of heart pathology.

Expression of type 1 (interferon gamma) and type 2 (interleukin-13, interleukin-5) cytokines at distinct stages of natural killer cell differentiation from progenitor cells

Blood ◽  
2002 ◽  
Vol 99 (4) ◽  
pp. 1273-1281 ◽  
Author(s):  
Matthew J. Loza ◽  
Loris Zamai ◽  
Livio Azzoni ◽  
Emanuela Rosati ◽  
Bice Perussia
Keyword(s):  
Cell Differentiation ◽  
Nk Cells ◽  
Interferon Gamma ◽  
Gm Csf ◽  
Type 2 Cytokines ◽  
Tnf Α ◽  
Ifn Γ

To determine whether production of type 1 and type 2 cytokines defines discrete stages of natural killer (NK) cell differentiation, cytokine expression was analyzed in human NK cells generated in vitro in the presence of interleukin-15 (IL-15) and/or IL-2 from umbilical cord blood hematopoietic progenitors. Like peripheral NK cells, the CD161+/CD56+ NK cells from these cultures contained a tumor necrosis factor alpha (TNF-α)+/granulocyte macrophage–colony-stimulating factor (GM-CSF)+ subset, an interferon gamma (IFN-γ)+ subset, mostly included within the former, and very few IFN-γ−/IL-13+ cells. Instead, most immature CD161+/CD56− NK cells, detectable only in the cultures with IL-2, produced IL-13, TNF-α, and GM-CSF, but not IFN-γ, and contained an IL-5+ subset. In short-term cultures with IL-12 and feeder cells, a proportion of the immature cells acquired the ability to produce IFN-γ. Part of these produced both IFN-γ and IL-13, irrespective of induced CD56 expression. These in vitro data indicate that ability to produce the type 2 cytokines IL-13 and IL-5 defines CD161+ NK cells at intermediate stages of differentiation, and is lost upon terminal functional differentiation, concomitant with acquired ability to produce IFN-γ.

scholarly journals IL-4 and IL-13 Negatively Regulate TNF-α- and IFN-γ-Induced β-Defensin Expression through STAT-6, Suppressor of Cytokine Signaling (SOCS)-1, and SOCS-3

2007 ◽  
Vol 179 (2) ◽  
pp. 984-992 ◽  
Author(s):  
Cristina Albanesi ◽  
Heather R. Fairchild ◽  
Stefania Madonna ◽  
Claudia Scarponi ◽  
Ornella De Pità ◽  
...  
Keyword(s):  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Tnf Α ◽  
Ifn Γ

Dendritic Cells Matured with a TLR7/8 Agonist Induce T Helper 1 Cell Polarization, Activate NK Cells and Are Thus Highly Suitable for Application in Cancer Immunotherapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 358-358
Author(s):  
Felix S Lichtenegger ◽  
Katharina Mueller ◽  
Wolfgang Hiddemann ◽  
Dolores J Schendel ◽  
Marion Subklewe
Keyword(s):  
Nk Cells ◽  
T Helper Cells ◽  
T Helper ◽  
T Helper 1 ◽  
Helper Cells ◽  
Tnf Α ◽  
Ifn Γ ◽  
Low Levels

Abstract Abstract 358FN2 Dendritic cells (DCs) are important regulators of the human immune response. By means of direct intercellular interactions and secretion of cytokines, they can induce a stimulatory or a regulatory response, depending on the environment in which they developed. In vitro, it is possible to imitate this process by addition of various cytokines. The aim of this study was to evaluate DCs matured by different cytokine cocktails for expression of immunostimulatory and -inhibitory molecules and correspondent activation of T helper 1 (Th1) and natural killer (NK) cells. The selection of these cocktails was guided by potential clinical application and usage in a GMP setting. We compared three different ways of DC generation from peripheral blood monocytes of healthy donors: 1) maturation by a cocktail including the TLR7/8 agonist R848 (TLR-mDCs), 2) DC generation by the standard combination of proinflammatory cytokines (IL-4, GM-CSF, IL-1β, PGE2, TNF-α, and IL-6) applied in many clinical studies so far (cc-mDCs), and 3) addition of IL-10 in order to induce a more regulatory phenotype (IL10-mDCs). The expression of a broad range of costimulatory and coinhibitory molecules (CD80, CD86, CD273, CD274, CD275, CD276, B7-H4, HVEM, CD30L, CD70, CD134L = OX40L, CD137L = 4-1BBL) on the surface of these DC populations was analyzed by FACS. Secretion of various cytokines crucial for interaction with other immune cells (IL-12p70, IL-10, TNF-α, IFN-γ, IL-2, and TGF-β) was measured by cytometric bead array after stimulation with CD40 ligand. In order to assess the functional importance of these signals, we performed in vitro polarization assays for T helper cells after co-culture with DCs and measured the in vitro stimulatory potential of the DCs for natural killer (NK) cells by CD69 upregulation and intracellular IFN-γ staining. We could show that TLR-mDCs were characterized by a predominance of costimulatory (e.g. CD80, CD86) relative to coinhibitory molecules (e.g. CD273, CD274, HVEM). When stimulated by CD40L, they displayed a cytokine profile with very high IL-12p70 and TNF-α, but little if any IL-10 production. In a co-culture with autologous T cells, the combination of these signals resulted in a strong polarization toward IFN-γ secreting Th1 cells, with little or no stimulation of Th2 and Th17 cells. The costimulatory profile of cc-mDCs, in comparison, was shifted toward a lower expression of costimulatory molecules and similar or higher expression of coinhibitory molecules (ratio of CD86 to CD273 expression around 40 compared to > 60 for TLR-mDCs, p < 0.005). No IL-12p70 and low levels of IL-10 were secreted. These signals were reflected in a less pronounced type 1 polarization of T helper cells. IL10-mDCs expressed very low levels of CD80 and CD86 and displayed a coinhibitory molecule pattern similar to cc-mDCs. Additionally, they secreted the immunoregulatory molecule IL-10 in higher amounts and did not activate T helper cells at all. As IL-12p70 is an important factor for NK cell activation, only TLR-mDCs were capable of upregulating the activation marker CD69 on NK cells and inducing significant secretion of IFN-γ. Both Th1 and NK cells play an important role in tumor defense. With this set of data, we clearly showed that TLR-mDCs, in consequence of their positive costimulatory profile and their high IL-12p70 secretion, are superior with respect to type 1 polarization of T cells and activation of NK cells. They are therefore highly suitable for application in cancer immunotherapy. This DC type will be used in a phase I/II trial for postremission therapy in patients with non-favorable AML, which will start in our clinic in 2012. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Decitabine Promotes Modulation in Phenotype and Function of Monocytes and Macrophages That Drive Immune Response Regulation

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 868
Author(s):  
Fabiana Albani Zambuzi ◽  
Priscilla Mariane Cardoso-Silva ◽  
Ricardo Cardoso Castro ◽  
Caroline Fontanari ◽  
Flavio da Silva Emery ◽  
...  
Keyword(s):  
Immune Response ◽  
Hematological Malignancies ◽  
M2 Macrophage ◽  
M2 Polarization ◽  
Tnf Α ◽  
Monocytes And Macrophages ◽  
Ifn Γ ◽  
And Function ◽  
The Impact

Decitabine is an approved hypomethylating agent used for treating hematological malignancies. Although decitabine targets altered cells, epidrugs can trigger immunomodulatory effects, reinforcing the hypothesis of immunoregulation in treated patients. We therefore aimed to evaluate the impact of decitabine treatment on the phenotype and functions of monocytes and macrophages, which are pivotal cells of the innate immunity system. In vitro decitabine administration increased bacterial phagocytosis and IL-8 release, but impaired microbicidal activity of monocytes. In addition, during monocyte-to-macrophage differentiation, treatment promoted the M2-like profile, with increased expression of CD206 and ALOX15. Macrophages also demonstrated reduced infection control when exposed to Mycobacterium tuberculosis in vitro. However, cytokine production remained unchanged, indicating an atypical M2 macrophage. Furthermore, when macrophages were cocultured with lymphocytes, decitabine induced a reduction in the release of inflammatory cytokines such as IL-1β, TNF-α, and IFN-γ, maintaining IL-10 production, suggesting that decitabine could potentialize M2 polarization and might be considered as a therapeutic against the exacerbated immune response.

scholarly journals Development of a Bioartificial Vascular Pancreas

2021 ◽  
Vol 12 ◽  
pp. 204173142110277
Author(s):  
Edward X Han ◽  
Juan Wang ◽  
Mehmet Kural ◽  
Bo Jiang ◽  
Katherine L Leiby ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Pancreatic Islets ◽  
Vascular Graft ◽  
Term Treatment ◽  
Diffusion Limitations ◽  
Human Scale ◽  
Arterial Blood ◽  
Long Term Treatment

Transplantation of pancreatic islets has been shown to be effective, in some patients, for the long-term treatment of type 1 diabetes. However, transplantation of islets into either the portal vein or the subcutaneous space can be limited by insufficient oxygen transfer, leading to islet loss. Furthermore, oxygen diffusion limitations can be magnified when islet numbers are increased dramatically, as in translating from rodent studies to human-scale treatments. To address these limitations, an islet transplantation approach using an acellular vascular graft as a vascular scaffold has been developed, termed the BioVascular Pancreas (BVP). To create the BVP, islets are seeded as an outer coating on the surface of an acellular vascular graft, using fibrin as a hydrogel carrier. The BVP can then be anastomosed as an arterial (or arteriovenous) graft, which allows fully oxygenated arterial blood with a pO2 of roughly 100 mmHg to flow through the graft lumen and thereby supply oxygen to the islets. In silico simulations and in vitro bioreactor experiments show that the BVP design provides adequate survivability for islets and helps avoid islet hypoxia. When implanted as end-to-end abdominal aorta grafts in nude rats, BVPs were able to restore near-normoglycemia durably for 90 days and developed robust microvascular infiltration from the host. Furthermore, pilot implantations in pigs were performed, which demonstrated the scalability of the technology. Given the potential benefits provided by the BVP, this tissue design may eventually serve as a solution for transplantation of pancreatic islets to treat or cure type 1 diabetes.

Sign in / Sign up

Export Citation Format

Share Document