Activation of latent transforming growth factor‐β1 by nitric oxide in macrophages: Role of soluble guanylate cyclase and MAP kinases
- 6 July 2009
- journal article
- Published by Wiley in Wound Repair and Regeneration
- Vol. 17 (4), 578-588
- https://doi.org/10.1111/j.1524-475x.2009.00509.x
Abstract
The inducible nitric oxide (NO) synthase and the cytokine transforming growth factor-β1 (TGF-β1), both central modulators of wound healing, interact reciprocally: TGF-β1 generally suppresses iNOS expression, while NO can induce and activate latent TGF-β1. We have shown that chemical NO activates recombinant human latent TGF-β1 by S-nitrosation of the latency-associated peptide (LAP), a cleaved portion of pro-TGF-β1 that maintains TGF-β1 in a biologically-inactive state. We hypothesized that cell-associated TGF-β1 could be activated by NO via known NO-inducible signaling pathways (soluble guanylate cyclase [sGC] and mitogen-activated protein [MAP] kinases). Treatment of mouse RAW 264.7 macrophage-like cells with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) led to a dose- and time-dependent increase in cell-associated active and latent TGF-β1, as assessed by quantitative immunocytochemistry for active TGF-β1 vs. LAP and partially validated by western blot analysis. Treatment with the sGC inhibitor 1,H-[1,2,4]oxadiazole[4,3-a]quinoxalon-1-one (ODQ) reduced both active and latent TGF-β1 dose-dependently. SNAP, in the presence or absence of ODQ or the MAP kinase inhibitors, did not affect steady-state TGF-β1 mRNA levels. Treatment with inhibitors specific for JNK1/2, ERK1/2, and p38 MAP kinases suppressed SNAP-induced active and latent TGF-β1. Treatment with the cell-permeable cGMP analog 8-Br-cGMP increased both active and latent TGF-β1. However, TGF-β1 activation induced by 8-Br-cGMP was not blocked by MAP kinase inhibitors. Our findings suggest that NO activates latent TGF-β1 via activation of sGC and generation of cGMP and separately via MAP kinase activation, and may shed insight into the mechanisms by which both cGMP production and MAP kinase activation enhance wound healing.Keywords
This publication has 36 references indexed in Scilit:
- Transforming growth factor-β in critical illnessCritical Care Medicine, 2005
- Nitric Oxide and cGMP Mediate α1D-Adrenergic Receptor–Stimulated Protein Secretion and p42/p44 MAPK Activation in Rat Lacrimal GlandPublished by Association for Research in Vision and Ophthalmology (ARVO) ,2005
- New insights into TGF-β–Smad signallingTrends in Biochemical Sciences, 2004
- Mechanisms of Cell Signaling by Nitric Oxide and Peroxynitrite: From Mitochondria to MAP KinasesAntioxidants and Redox Signaling, 2001
- Involvement of the p38 Mitogen-activated Protein Kinase Pathway in Transforming Growth Factor-β-induced Gene ExpressionPublished by Elsevier BV ,1999
- Control of Nitric Oxide Production by Transforming Growth Factor-β1: Mechanistic Insights and Potential Relevance to Human DiseaseNitric Oxide, 1997
- Latency and activation in the control of TGF-βJournal of Mammary Gland Biology and Neoplasia, 1996
- Redox-mediated activation of latent transforming growth factor-beta 1Molecular Endocrinology, 1996
- Parallel signal processing among mammalian MAPKsTrends in Biochemical Sciences, 1995
- p53 expression in nitric oxide‐induced apoptosisFEBS Letters, 1994