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

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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A histone deacetylase inhibitor, largazole, decreases liver fibrosis and angiogenesis by inhibiting transforming growth factor-β and vascular endothelial growth factor signalling

Liver International ◽

10.1111/liv.12034 ◽

2012 ◽

Vol 33 (4) ◽

pp. 504-515 ◽

Cited By ~ 57

Author(s):

Yuqing Liu ◽

Zhuo Wang ◽

Jianing Wang ◽

Wingchi Lam ◽

Shuqin Kwong ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Liver Fibrosis ◽

Histone Deacetylase Inhibitor ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Vascular Endothelial ◽

Deacetylase Inhibitor ◽

Growth Factor Signalling ◽

Endothelial Growth Factor

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Identification of tgh-2, a Filarial Nematode Homolog of Caenorhabditis elegans daf-7 and Human Transforming Growth Factor β, Expressed in Microfilarial and Adult Stages of Brugia malayi

Infection and Immunity ◽

10.1128/iai.68.11.6402-6410.2000 ◽

2000 ◽

Vol 68 (11) ◽

pp. 6402-6410 ◽

Cited By ~ 119

Author(s):

Natalia Gomez-Escobar ◽

William F. Gregory ◽

Rick M. Maizels

Keyword(s):

Caenorhabditis Elegans ◽

Growth Factor ◽

Transforming Growth Factor ◽

Expressed Sequence Tag ◽

Signal Sequence ◽

Brugia Malayi ◽

Transforming Growth Factor Β ◽

Lung Epithelial Cells ◽

Filarial Nematode ◽

Mature Adult

ABSTRACT A novel member of the transforming growth factor β (TGF-β) family has been identified in the filarial nematode parasiteBrugia malayi by searching the recently developed Expressed Sequence Tag (EST) database produced by the Filarial Genome Project. Designated tgh-2, this new gene shows most similarity to a key product regulating dauer larva formation in Caenorhabditis elegans (DAF-7) and to the human down-modulatory cytokine TGF-β. Homology to DAF-7 extends throughout the length of the 349-amino-acid (aa) protein, which is divided into an N-terminal 237 aa, including a putative signal sequence, a 4-aa basic cleavage site, and a 108-aa C-terminal active domain. Similarity to human TGF-β is restricted to the C-terminal domain, over which there is a 32% identity between TGH-2 and TGF-β1, including every cysteine residue. Expression of tgh-2 mRNA has been measured over the filarial life cycle. It is maximal in the microfilarial stage, with lower levels of activity around the time of molting within the mammal, but continues to be expressed by mature adult male and female parasites. Expression in both the microfilaria, which is in a state of arrested development, and the adult, which is terminally differentiated, indicates that tgh-2 may play a role other than purely developmental. This is consistent with our observation that TGH-2 is secreted by adult worms in vitro. Recombinant TGH-2 expressed in baculovirus shows a low level of binding to TGF-β-receptor bearing mink lung epithelial cells (MELCs), which is partially inhibited (16 to 39%) with human TGF-β, and activates plasminogen activator inhibitor-1 transcription in MELCs, a marker for TGF-β-mediated transduction. Further tests will be required to establish whether the major role of B. malayi TGH-2 (Bm-TGH-2) is to modulate the host immune response via the TGF-β pathway.

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RNA Interference Targeting Transforming Growth Factor-β Enhances NKG2D-Mediated Antiglioma Immune Response, Inhibits Glioma Cell Migration and Invasiveness, and Abrogates Tumorigenicity In vivo

Cancer Research ◽

10.1158/0008-5472.can-04-1627 ◽

2004 ◽

Vol 64 (20) ◽

pp. 7596-7603 ◽

Cited By ~ 202

Author(s):

Manuel A. Friese ◽

Jörg Wischhusen ◽

Wolfgang Wick ◽

Markus Weiler ◽

Günter Eisele ◽

...

Keyword(s):

Immune Response ◽

Cell Migration ◽

Rna Interference ◽

Growth Factor ◽

Glioma Cell ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Glioma Cell Migration

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Transforming Growth Factor-β and the Immune Response to Malignant Disease

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-07-1654 ◽

2007 ◽

Vol 13 (21) ◽

pp. 6247-6251 ◽

Cited By ~ 102

Author(s):

Beverly A. Teicher

Keyword(s):

Immune Response ◽

Growth Factor ◽

Malignant Disease ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β

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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 ◽

10.1128/mbio.00095-11 ◽

2011 ◽

Vol 2 (3) ◽

Cited By ~ 24

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.

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