scholarly journals Diversion of the Immune Response to Neisseria gonorrhoeae from Th17 to Th1/Th2 by Treatment with Anti-Transforming Growth Factor β Antibody Generates Immunological Memory and Protective Immunity

mBio ◽  
2011 ◽  
Vol 2 (3) ◽  
Author(s):  
Yingru Liu ◽  
Michael W. Russell
Keyword(s):  
Immune Response ◽  
Growth Factor ◽  
Neisseria Gonorrhoeae ◽  
Primary Infection ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Content Type ◽  
Th2 Responses ◽  
Th1 And Th2 Responses ◽  
Th1 And Th2

ABSTRACTThe immune response toNeisseria gonorrhoeaeis poorly understood, but its extensive antigenic variability and resistance to complement are thought to allow it to evade destruction by the host’s immune defenses. We propose thatN. gonorrhoeaealso avoids inducing protective immune responses in the first place. We previously found thatN. gonorrhoeaeinduces interleukin-17 (IL-17)-dependent innate responses in mice and suppresses Th1/Th2-dependent adaptive responses in murine cellsin vitrothrough the induction of transforming growth factor β (TGF-β). In this study using a murine model of vaginal gonococcal infection, mice treated with anti-TGF-β antibody during primary infection showed accelerated clearance ofN. gonorrhoeae, with incipient development of Th1 and Th2 responses and diminished Th17 responses in genital tract tissue. Upon secondary reinfection, mice that had been treated with anti-TGF-β during primary infection showed anamnestic recall of both Th1 and Th2 responses, with the development of antigonococcal antibodies in sera and secretions, and enhanced resistance to reinfection. In mouse knockout strains defective in Th1 or Th2 responses, accelerated clearance of primary infection due to anti-TGF-β treatment was dependent on Th1 activity but not Th2 activity, whereas resistance to secondary infection resulting from anti-TGF-β treatment during primary infection was due to both Th1- and Th2-dependent memory responses. We propose thatN. gonorrhoeaeproactively elicits Th17-driven innate responses that it can resist and concomitantly suppresses Th1/Th2-driven specific adaptive immunity that would protect the host. Blockade of TGF-β reverses this pattern of host immune responsiveness and facilitates the emergence of protective antigonococcal immunity.IMPORTANCEPathogen-host interactions during infectious disease are conventionally thought of as two-way reactions, that of the host against the pathogen and vice versa, with the outcome dependent on which one ultimately prevails. We propose thatNeisseria gonorrhoeae, a pathogen that has become extremely well adapted to its exclusive human host, proactively directs the manner in which the host responds in ways that are beneficial to its own survival but detrimental to the host. Gonorrhea is a widely prevalent sexually transmitted infection, and naturally occurring gonococcal strains are becoming resistant to most available antibiotics, yet no effective vaccine has been developed. These new insights into the immune response toN. gonorrhoeaeshould lead to novel therapeutic strategies and facilitate new approaches to vaccine development.

scholarly journals Trypanosoma cruzi Induces the PARP1/AP-1 Pathway for Upregulation of Metalloproteinases and Transforming Growth Factor β in Macrophages: Role in Cardiac Fibroblast Differentiation and Fibrosis in Chagas Disease

mBio ◽  
2020 ◽  
Vol 11 (6) ◽  
Author(s):  
Subhadip Choudhuri ◽  
Nisha Jain Garg
Keyword(s):  
Growth Factor ◽  
Chagas Disease ◽  
Transcriptional Activation ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cardiac Fibroblast ◽  
Myofibroblast Differentiation ◽  
Content Type ◽  
Parp1 Inhibitors

ABSTRACT Chagas disease (CD), caused by Trypanosoma cruzi, is a degenerative heart condition. In the present study, we investigated the role of poly [ADP-ribose] polymerase 1/activator protein 1 (PARP1/AP-1) in upregulation of profibrotic macrophages (Mϕ) and subsequent development of cardiac fibrosis in CD. We used in vitro and in vivo models of T. cruzi infection and chemical and genetic inhibition of Parp1 to examine the molecular mechanisms by which Mϕ might augment profibrotic events in CD. Cultured (RAW 264.7 and THP-1) Mϕ infected with T. cruzi and primary cardiac and splenic Mϕ of chronically infected mice exhibited a significant increase in the expression, activity, and release of metalloproteinases (MMP2, MMP9, and MMP12) and the cytokine transforming growth factor β (TGF-β). Mϕ release of MMPs and TGF-β signaled the cardiac fibroblast to myofibroblast differentiation, as evidenced by a shift from S100A4 to alpha smooth muscle actin (α-SMA) expression. Incubation of infected Mϕ with MMP2 and MMP9 inhibitors resulted in 60 to 74% decline in TGF-β release, and MMP9 and PARP1 inhibitors resulted in 57 to 70% decline in Mϕ TGF-β-driven cardiac fibroblast differentiation. Likewise, histological studies showed a 12- to 16-fold increase in myocardial expression of CD68 (Mϕ marker) and its colocalization with MMP9/TGF-β, galectin-3, and vimentin in wild-type mice with CD. In comparison, chronically infected Parp1−/− mice exhibited a >50% decline in myocardial levels of Mϕ and associated fibrosis markers. Further study showed that PARP1 synergized with c-Fos and JunB AP-1 family members for transcriptional activation of profibrotic response after T. cruzi infection. We conclude that PARP1 inhibition offers a potential therapy for controlling the T. cruzi-driven fibroblast differentiation in CD through modulation of the Mϕ signaling of the AP-1–MMP9–TGF-β pathway. IMPORTANCE Cardiomyopathy is the most important clinical manifestation of T. cruzi-driven CD. Recent studies have suggested the detrimental role of the matrix metalloproteinases MMP2 and MMP9 in extracellular matrix (ECM) degradation during cardiac remodeling in T. cruzi infection. Peripheral TGF-β levels are increased in clinically symptomatic CD patients over those in clinically asymptomatic seropositive individuals. We provide the first evidence that during T. cruzi infection, Mϕ release of MMP2 and MMP9 plays an active role in activation of TGF-β signaling of ECM remodeling and cardiac fibroblast-to-myofibroblast differentiation. We also determined that PARP1 signals c-Fos- and JunB-mediated AP-1 transcriptional activation of profibrotic gene expression and demonstrated the significance of PARP1 inhibition in controlling chronic fibrosis in Chagas disease. Our study provides a promising therapeutic approach for controlling T. cruzi-driven fibroblast differentiation in CD by PARP1 inhibitors through modulation of the Mϕ signaling of the AP-1–MMP9–TGF-β pathway.

scholarly journals Expression and Function of Transforming Growth Factor β in Melioidosis

2012 ◽  
Vol 80 (5) ◽  
pp. 1853-1857 ◽  
Author(s):  
Tassili A. F. Weehuizen ◽  
Catharina W. Wieland ◽  
Gerritje J. W. van der Windt ◽  
Jan-Willem Duitman ◽  
Louis Boon ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Organ Injury ◽  
Antibody Treatment ◽  
Content Type ◽  
Smad2 Phosphorylation ◽  
Distant Organ ◽  
Proinflammatory Role ◽  
And Function

ABSTRACTMelioidosis, caused by the Gram-negative bacteriumBurkholderia pseudomallei, is an important cause of community-acquired sepsis in Southeast Asia and northern Australia. An important controller of the immune system is the pleiotropic cytokine transforming growth factor β (TGF-β), of which Smad2 and Smad3 are the major signal transducers. In this study, we aimed to characterize TGF-β expression and function in experimental melioidosis. TGF-β expression was determined in 33 patients with culture-proven infection withB. pseudomalleiand 30 healthy controls. We found that plasma TGF-β concentrations were strongly elevated during melioidosis. In line with this finding, TGF-β expression in C57BL/6 mice intranasally inoculated withB. pseudomalleiwas enhanced as well. To assess the role of TGF-β, we inhibited TGF-β using a selective murine TGF-β antibody. Treatment of mice with anti-TGF-β antibody resulted in decreased lung Smad2 phosphorylation. TGF-β blockade appeared to be protective: mice treated with anti-TGF-β antibody and subsequently infected withB. pseudomalleishowed diminished bacterial loads. Moreover, less distant organ injury was observed in anti-TGF-β treated mice as shown by reduced blood urea nitrogen (BUN) and aspartate transaminase (AST) values. However, anti-TGF-β treatment did not have an effect on survival. In conclusion, TGF-β is upregulated duringB. pseudomalleiinfection and plays a limited but proinflammatory role during experimental melioidosis.

Effect of a single high-dose gamma irradiation on cultured cells in human cerebral arteriovenous malformation

2002 ◽  
Vol 97 ◽  
pp. 459-463 ◽  
Author(s):  
Otto Major ◽  
György T. Szeifert ◽  
Ilona Fazekas ◽  
Dusan Vitanovics ◽  
Éva Csonka ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Gamma Irradiation ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cerebral Arteriovenous Malformation ◽  
High Dose ◽  
Content Type ◽  
Single High Dose ◽  
Fine Print

Object. The purpose of this study was to analyze the effect of single high-dose gamma irradiation at a cellular biological level on tissue cultures obtained in patients who underwent surgery for cerebral arteriovenous malformation (AVM). Methods. The cell proliferation indices and changes in activation of p53, p21Waf-1, and mdm-2 were determined. Additionally, immunohistochemical investigations for vimentin, desmin, α—smooth muscle actin (α-SMA), glial fibrillary acidic protein, Factor VIII—related antigen (F-VIII), cytokeratin, S100, and transforming growth factor—β (TGFβ) were performed on cultured AVM cells after a single high-dose irradiation. Normal human brain microvessel endothelial (HBE) cells and aortic smooth muscle cells served as controls. The proliferation index decreased on the 5th day after irradiation and remained depressed over the observation period in the irradiated AVM cultures. The p53, p21Waf-1, and mdm-2 messenger RNA measurements showed considerable elevation both in AVM cultures and HBE cells after 15-Gy irradiation, which indicated apoptosis. Immunohistochemistry revealed strong vimentin positivity in the nonirradiated cultures, which gradually decreased in the irradiated cultures. Transforming growth factor—β positivity was demonstrated in the irradiated specimens, indicating transformation of fibroblastic cells into activated myofibroblastic elements. This transformation was confirmed by demonstrating elevated SMA expression as well in the radiation-treated fibroblasts. Conclusions. The presence of TGFβ and α-SMA activity in the irradiated AVM cells suggests that along with the genetically confirmed apoptotic activity, fibroblast transformation into myofibroblasts might be one of the mechanisms leading to shrinkage and obliteration of AVMs after single high-dose gamma irradiation.

Transforming growth factor-β-like activity in tumors of the central nervous system

1988 ◽  
Vol 68 (6) ◽  
pp. 920-924 ◽  
Author(s):  
W. Craig Clark ◽  
Joseph Bressler
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Molecular Level ◽  
Tumor Cell Line ◽  
Transforming Growth Factor Β ◽  
Glial Tumor ◽  
Content Type ◽  
The Central Nervous System ◽  
Factor Type ◽  
Regulatory Functions

✓ Transforming growth factor type β (TGF-β) is a ubiquitous peptide with wide-ranging regulatory functions. This paper reports the initial isolation of TGF-β activity from human glial and mesenchymally derived tumors and a human glial tumor cell line. While its physiological function at the molecular level is not yet defined, it is believed that this peptide plays a central role in the control of growth and transformation, with the exact role it plays being a function of the entire set of growth factors present in a given cell.

scholarly journals Transforming growth factor β and apoptosis in leprosy skin lesions: possible relationship with the control of the tissue immune response in the Mycobacterium leprae infection

2012 ◽  
Vol 14 (9) ◽  
pp. 696-701 ◽  
Author(s):  
Juarez Antonio Simoes Quaresma ◽  
Fabrício Anderson Carvalho de Almeida ◽  
Tinara Leila de Souza Aarao ◽  
Luis Paulo de Miranda Araujo Soares ◽  
Ismaelino Mauro Nunes Magno ◽  
...  
Keyword(s):  
Immune Response ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mycobacterium Leprae ◽  
Transforming Growth Factor Β ◽  
Skin Lesions

scholarly journals SMA-10 Is a Non-Canonical Member of the TGF-β Sma/Mab Pathway and Immunity Regulator via the DAF-2 Insulin Receptor in Caenorhabditis elegans

2021 ◽  
Vol 22 (2) ◽  
pp. 638
Author(s):  
María Pilar de Lucas ◽  
Marta Jiménez ◽  
Paloma Sánchez-Pavón ◽  
Alberto G. Sáez ◽  
Encarnación Lozano
Keyword(s):  
Immune Response ◽  
Body Size ◽  
Caenorhabditis Elegans ◽  
Growth Factor ◽  
Insulin Receptor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Small Male ◽  
Positive Modulator ◽  
Growth Factor Signalling

Transforming growth factor β (TGF-β) signalling pathways are highly conserved across metazoa and play essential roles not only during development but also in adult tissue maintenance. Alterations of these pathways usually result in a plethora of pathologies. In the nematode Caenorhabditis elegans, the TGF-β Sma/Mab (small/male abnormal) pathway regulates various worm phenotypes such as body size, immune response, ageing, matricide and reproductive span. SMA-10 has been described as a positive modulator of worm body size through the TGF-β Sma/Mab pathway. To better understand if SMA-10 is a core component of the pathway, we use gene epistatic analysis to assess the contribution of SMA-10 to various phenotypes regulated by TGF-β Sma/Mab. We confirm that SMA-10 controls body size and find that it also affects the matricide and reproductive span of the nematodes. However, neither male tail formation (previously reported) nor ageing appeared altered. Lastly, although null sma-10 worms are more susceptible to Pseudomonas aeruginosa infections than wild-types, this response does not depend on TGF-β Sma/Mab but on the insulin receptor DAF-2. We also show that the expression of sma-10 in either hypodermis or intestine fully rescues the wild-type immune response. Our results contribute to understanding the role of SMA-10 as a context-dependent component of TGF-β Sma/Mab, and reveal a function of SMA-10 in immunity in association to the Insulin/insulin-like growth factor signalling (IIS) pathway.

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