IL-7 inhibits fibroblast TGF-β production and signaling in pulmonary fibrosis

Huang, Min; Sharma, Sherven; Zhu, Li; Keane, Michael P.; Luo, Jianxun; Zhang, Ling; Burdick, Marie D.; Lin, Ying Q.; Dohadwala, Mariam; Gardner, Brian; Batra, Raj K.; Strieter, Robert M.; Dubinett, Steven M.

doi:10.1172/jci200214685

Cited by 59 publications

(62 citation statements)

References 34 publications

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“…In our study, IL-7 significantly decreased the expression of TGF-␤. IL-7 also decreases TGF-␤ expression in murine models of pulmonary fibrosis (70,71). TGF-␤ potentiates HIV infection (72) and is directly immunosuppressive.…”

Section: Discussionmentioning

confidence: 98%

Interleukin-15 but Not Interleukin-7 Abrogates Vaccine-Induced Decrease in Virus Level in Simian Immunodeficiency Virusmac251-Infected Macaques

Hryniewicz

Price

Moniuszko

et al. 2007

The Journal of Immunology

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The loss of CD4+ T cells and the impairment of CD8+ T cell function in HIV infection suggest that pharmacological treatment with IL-7 and IL-15, cytokines that increase the homeostatic proliferation of T cells and improve effector function, may be beneficial. However, these cytokines could also have a detrimental effect in HIV-1-infected individuals, because both cytokines increase HIV replication in vitro. We assessed the impact of IL-7 and IL-15 treatment on viral replication and the immunogenicity of live poxvirus vaccines in SIVmac251-infected macaques (Macaca mulatta). Neither cytokine augmented the frequency of vaccine-expanded CD4+ or CD8+ memory T cells, clonal recruitment to the SIV-specific CD8+ T cell pool, or CD8+ T cell function. Vaccination alone transiently decreased the viral set point following antiretroviral therapy suspension. IL-15 induced massive proliferation of CD4+ effector T cells and abrogated the ability of vaccination to decrease set point viremia. In contrast, IL-7 neither augmented nor decreased the vaccine effect and was associated with a decrease in TGF-β expression. These results underscore the importance of testing immunomodulatory approaches in vivo to assess potential risks and benefits for HIV-1-infected individuals.

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Section: Discussionmentioning

confidence: 98%

Interleukin-15 but Not Interleukin-7 Abrogates Vaccine-Induced Decrease in Virus Level in Simian Immunodeficiency Virusmac251-Infected Macaques

Hryniewicz

Price

Moniuszko

et al. 2007

The Journal of Immunology

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“…However, induction of Smad7 by TNF-␣ may not occur in all cell types. For example, TNF-␣-dependent activation of NF-B actually inhibited Smad7 expression in human embryonic kidney 293 cells (Nagarajan et al, 2000), whereas Smad7 levels did not noticeably increase in human dermal fibroblasts or chondrocytes after treatment with TNF-␣ (Verrecchia et al, 2000;Huang et al, 2002;RomanBlas et al, 2007). To examine whether Smad7 expression in human pulmonary fibroblasts was altered by TNF-␣, quiescent cells in low-serum medium were treated with 10 ng/ml TNF-␣ and then evaluated for Smad7 expression by immunoblot analysis.…”

Section: Tnf-␣ Inhibits Tgf␤1-inducible Sm␣a Gene Activity In Human Pmentioning

confidence: 99%

Transforming Growth Factor β1-mediated Activation of the Smooth Muscle α-Actin Gene in Human Pulmonary Myofibroblasts Is Inhibited by Tumor Necrosis Factor-α via Mitogen-activated Protein Kinase Kinase 1-dependent Induction of the Egr-1 Transcriptional Repressor

Kelm

Strauch

2009

MBoC

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Transforming growth factor (TGF) ␤1 is a mediator of myofibroblast differentiation in healing wounds in which it activates transcription of the smooth muscle ␣-actin (SM␣A) gene via dynamic interplay of nuclear activators and repressors. Targeting components of TGF␤1 signaling may be an effective strategy for controlling myofibroblasts in chronic fibrotic diseases. We examined the ability of proinflammatory tumor necrosis factor (TNF)-␣ to antagonize TGF␤1-mediated human pulmonary myofibroblast differentiation. TNF-␣ abrogated TGF␤1-induced SM␣A gene expression at the level of transcription without disrupting phosphorylation of regulatory Smads. Intact mitogen-activated protein kinase kinase (Mek)-extracellular signal-regulated kinase (Erk) kinase signaling was required for myofibroblast repression by TNF-␣ via induction of the early growth response factor-1 (Egr-1) DNA-binding protein. Egr-1 bound to the GC-rich SPUR activation element in the SM␣A promoter and potently suppressed Smad3-and TGF␤1-mediated transcription. Reduction in Smad binding to the SM␣A promoter in TNF-␣-treated myofibroblasts was accompanied by an increase in Egr-1 and YB-1 repressor binding, suggesting that the molecular mechanism underlying repression may involve competitive interplay between Egr-1, YB-1, and Smads. The ability of TNF-␣ to attenuate myofibroblast differentiation via modulation of a Mek1/Erk/Egr-1 regulatory axis may be useful in designing new therapeutic targets to offset destructive tissue remodeling in chronic fibrotic disease. INTRODUCTIONMyofibroblasts are specialized stromal cells that synthesize interstitial collagens and contain a smooth muscle ␣-actin (SM␣A)-enriched contractile apparatus designed to generate tensile force needed for wound closure and tissue healing (Skalli and Gabbiani, 1988;Ronnov-Jessen and Petersen, 1996;Zalewski and Shi, 1997;Gabbiani, 2003;Desmouliere et al., 2005;Tomasek et al., 2006). Transforming growth factor (TGF) ␤1) is the principle mediator of myofibroblast differentiation in healing wounds where it accumulates in granulation tissue in activated form during leukocyte infiltration and potently stimulates transcription of the type I␣2 collagen subunit (COL1␣2) and SM␣A genes (Becker et al., 2000;Massague and Wotton, 2000;Cogan et al., 2002;Higashi et al., 2003;Grotendorst et al., 2004;Leask and Abraham, 2004;Subramanian et al., 2004;Zhang et al., 2005). Smad proteins 2 and 3 are activated by TGF␤1 receptor engagement and enter the nucleus in which they directly bind SM␣A and COL1␣2 promoter DNA. Smad3 also reportedly forms additional off-promoter complexes with DNA-binding repressor proteins to govern transcriptional output of the COL1␣2 gene in TGF␤1-activated myofibroblasts (Higashi et al., 2003). Poor termination of TGF␤1-mediated myofibroblast differentiation could contribute to chronic fibroproliferative disease and excessive scar formation in the injured lung, heart, liver, kidney, and skin potentially causing pathobiologic phenomena referred to as "endless healing" (Tomasek et a...

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“…In vivo, this involves multiple mechanisms, which include the suppression of cytokines like IL-2 (D' Angeac et al, 1991;McKarns and Kaminski, 2000), IL-6 (Baroni et al, 2003), and IL-7 (Tang et al, 1997), each of which exert important effects on lymphocyte proliferation and viability. There is extensive crosstalk between intermediates in the TGF-b pathway and downstream targets of the receptors for these cytokines Ebert, 1999;Ohta et al, 2000;Huang et al, 2002;Wierenga et al, 2002;Baroni et al, 2003;Zhang et al, 2004). The Jak-Stat pathway of signal transducers acts downstream of receptors for the ILs and IFNs, and activation of the Jak-Stat cascade has, most commonly, a suppressive effect on TGF-b signaling (Ulloa et al, 1999;Eickelberg et al, 2001).…”

Section: Tgf-b Signaling In the Differentiation Of T-lymphocytesmentioning

confidence: 99%

TGF-β signaling in T cells: roles in lymphoid and epithelial neoplasia

Letterio

2005

Oncogene

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Transforming growth factor-b (TGF-b) plays an essential role in regulating the homeostasis of cells in the lymphoid lineage. TGF-b signaling is not required for normal thymopoiesis, but is essential for regulating the expansion, activation, and effector function of the mature CD4 þ and CD8 þ T cells in the peripheral lymphoid organs and target tissues. Recent studies in both mice and humans have elucidated an important and complex role for TGF-b in regulatory T-cell biology. Disruption of TGF-b signaling in T cells impairs the maintenance of regulatory T cells, results in the expansion of activated effector T cells, and is associated with the production of cytokines that have major effects on cells in their environment. While autoimmunity and inflammation are the principal phenotypes associated with the abrogation of TGF-b signaling in T cells in mice, emerging evidence now also directly links Smad-dependent TGF-b signaling in T cells to the suppression of epithelial neoplasia. The TGF-b receptor-activated Smad3 plays a critical role in mediating many of the inhibitory effects of TGF-b signaling in T cells, and has now been established as an important suppressor of leukemogenesis. These studies are increasing our awareness of the many complex mechanisms through which TGF-b signaling controls the pathogenesis of cancer.

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IL-7 inhibits fibroblast TGF-β production and signaling in pulmonary fibrosis

Cited by 59 publications

References 34 publications

Interleukin-15 but Not Interleukin-7 Abrogates Vaccine-Induced Decrease in Virus Level in Simian Immunodeficiency Virusmac251-Infected Macaques

Interleukin-15 but Not Interleukin-7 Abrogates Vaccine-Induced Decrease in Virus Level in Simian Immunodeficiency Virusmac251-Infected Macaques

Transforming Growth Factor β1-mediated Activation of the Smooth Muscle α-Actin Gene in Human Pulmonary Myofibroblasts Is Inhibited by Tumor Necrosis Factor-α via Mitogen-activated Protein Kinase Kinase 1-dependent Induction of the Egr-1 Transcriptional Repressor

TGF-β signaling in T cells: roles in lymphoid and epithelial neoplasia

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