Interleukin-7 and Transforming Growth Factor-β Play Counter-regulatory Roles in Protein Kinase C-δ-dependent Control of Fibroblast Collagen Synthesis in Pulmonary Fibrosis

Zhang, Ling; Keane, Michael P.; Zhu, Li; Sharma, Sherven; Rozengurt, Enrique; Strieter, Robert M.; Dubinett, Steven M.; Huang, Min

doi:10.1074/jbc.c400115200

Cited by 55 publications

(37 citation statements)

References 23 publications

(23 reference statements)

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“…5), indicating that PKC is pivotal for transdifferentiation of dermal fibroblasts to myofibroblasts. In line with this observation, TGF␤1 stimulated the induction of ␣2(I) collagen in human dermal fibroblasts (Jinnin et al, 2005) and of ␣1(I) collagen in human pulmonary fibroblasts (Zhang et al, 2004) through active PKC␦. Furthermore, Gao et al (Gao et al, 2003) showed that Journal of Cell Science 119 (13) differentiation of rat aortic fibroblasts to myofibroblasts was inhibited by the PKC inhibitor calphostin C. Differentiation was abolished by depleting the PKC␣ isoform by transfection with antisense PKC␣ oligonucleotides.…”

Section: Pkc Ros and Generation Of Myofibroblastssupporting

confidence: 52%

Enhancement of tumor invasion depends on transdifferentiation of skin fibroblasts mediated by reactive oxygen species

Cat

Stuhlmann

Steinbrenner

et al. 2006

Journal of Cell Science

110

102

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Myofibroblasts, pivotal for tumor progression, populate the microecosystem of reactive stroma. Using an in vitro tumor-stroma model of skin carcinogenesis, we report here that tumor-cell-derived transforming growth factor β1 (TGFβ1) initiates reactive oxygen species-dependent expression of α-smooth muscle actin, a biomarker for myofibroblastic cells belonging to a group of late-responsive genes. Moreover, protein kinase C (PKC) is involved in lipid hydroperoxide-triggered molecular events underlying transdifferentiation of fibroblasts to myofibroblasts (mesenchymal-mesenchymal transition, MMT). In contrast to fibroblasts, myofibroblasts secrete large amounts of hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6), resulting in a significant increase in the invasive capacity of tumor cells. The thiol N-acetyl-L-cysteine, the micronutrient selenite as well as selenoprotein P and the lipid peroxidation inhibitors α-tocopherol and butylated hydroxytoluene significantly lower both the number of TGFβ1-initiated myofibroblasts and the secretion of HGF, VEGF and IL-6, correlating with a diminished invasive capacity of tumor cells. This novel concept of stromal therapy, namely the protection of stromal cells against the dominating influence of tumor cells in tumor-stroma interaction by antioxidants and micronutrients, may form the basis for prevention of MMT in strategies for chemoprevention of tumor invasion.

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Section: Pkc Ros and Generation Of Myofibroblastssupporting

confidence: 52%

Enhancement of tumor invasion depends on transdifferentiation of skin fibroblasts mediated by reactive oxygen species

Cat

Stuhlmann

Steinbrenner

et al. 2006

Journal of Cell Science

110

102

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“…Data are means Ϯ SD. **P Ͻ 0.01. imply that PKC␦ activates Src in other cell types and that PKC␦-Src constitutes a signaling motif regulating diverse phenotypic responses including collagen type I accumulation (50), organization of the actin cytoskeleton (4), and podosome assembly (46). In our present studies, a selective inhibitor of PKC␦, rottlerin (12), prevented TGF-␤ from activating Src in HMC.…”

Section: Discussionmentioning

confidence: 52%

TGF-β-regulated collagen type I accumulation: role of Src-based signals

Mishra¹,

Zhu²,

Eckert³

et al. 2007

American Journal of Physiology-Cell Physiology

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Transforming growth factor-β (TGF-β) stimulates myofibroblast transdifferentiation, leading to type I collagen accumulation and fibrosis. We investigated the function of Src in TGF-β-induced collagen I accumulation. In human mesangial cells, PTyr416 Src (activated Src) was 3.3-fold higher in TGF-β-treated cells than in controls. Src activation by TGF-β was blocked by rottlerin and by a dominant negative mutant of protein kinase Cδ (PKCδ), showing that TGF-β activates Src by a PKCδ-based mechanism. Pharmacological inhibitors and a dominant negative Src mutant prevented the increase in collagen type I secretion in cells exposed to TGF-β. Similarly, on-target Src small interference RNA (siRNA) prevented type I collagen secretion in response to TGF-β, but off-target siRNA complexes had no effect. It is well established in mesangial cells that upregulation of type I collagen by TGF-β requires extracellular signal-regulated kinase 1/2 (ERK1/2), and we found that activation of ERK1/2 by TGF-β requires Src. In conclusion, these results suggest that stimulation of collagen type I secretion by TGF-β requires a PKCδ-Src-ERK1/2 signaling motif.

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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: 99%

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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Interleukin-7 and Transforming Growth Factor-β Play Counter-regulatory Roles in Protein Kinase C-δ-dependent Control of Fibroblast Collagen Synthesis in Pulmonary Fibrosis

Cited by 55 publications

References 23 publications

Enhancement of tumor invasion depends on transdifferentiation of skin fibroblasts mediated by reactive oxygen species

Enhancement of tumor invasion depends on transdifferentiation of skin fibroblasts mediated by reactive oxygen species

TGF-β-regulated collagen type I accumulation: role of Src-based signals

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

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