Crosstalk between TGF-β1 and complement activation augments epithelial injury in pulmonary fibrosis

Hongmei Gu, Elizabeth A. Mickler, Oscar W. Cummings, George E. Sandusky, Daniel J. Weber, Adam Gracon, Trent Woodruff, David S. Wilkes, Ragini Vittal

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

The epithelial complement inhibitory proteins (CIPs) cluster of differentiation 46 and 55 (CD46 and CD55) regulate circulating immune complex- mediated complement activation in idiopathic pulmonary fibrosis (IPF). Our previous studies demonstrated that IL-17A mediates epithelial injury via transforming growth factor β1 (TGF-β1) and down-regulates CIPs. In the current study, we examined the mechanistic role of TGF-β1 in complement activation- mediated airway epithelial injury in IPF pathogenesis. We observed lower epithelial CIP expression in IPF lungs compared to normal lungs, associated with elevated levels of complement component 3a and 5a (C3a and C5a), locally and systemically. In normal primary human small airway epithelial cells (SAECs) treated with TGF-β1 (10 ng/ml), C3a, or C5a (100 nM), we observed loss of CIPs and increased poly(ADP-ribose) polymerase (PARP) activation [also observed with RNA interference (RNAi) of CD46/CD55]. TGF-β1-mediated loss of CIPs and Snail induction [SNAI1; a transcriptional repressor of E-cadherin (E-CAD)] was blocked by inhibiting mitogen-activated protein kinase (p38MAPK; SB203580) and RNAi silencing of SNAI1. C3a- and C5a-mediated loss of CIPs was also blocked by p38MAPK inhibition. While C3a upregulated TGFb transcripts, both C3a and C5a down-regulated SMAD7 (negative regulator of TGF-β), and whereas TGF-β1 induced C3a/C5a receptor (C3aR/C5aR) expression, pharmacologic C3aR/C5aR inhibition protected against C3a-/C5a-mediated loss of CIPs. Taken together, our results suggest that epithelial injury in IPF can be collectively amplified as a result of TGF-β1- induced loss of CIPs leading to complement activation that down-regulates CIPs and induces TGF-β1 expression.

Original languageEnglish (US)
Pages (from-to)4223-4234
Number of pages12
JournalFASEB Journal
Volume28
Issue number10
DOIs
StatePublished - Oct 1 2014

Keywords

  • C3a
  • C5a
  • CD46
  • CD55
  • IPF

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology
  • Medicine(all)

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    Gu, H., Mickler, E. A., Cummings, O. W., Sandusky, G. E., Weber, D. J., Gracon, A., Woodruff, T., Wilkes, D. S., & Vittal, R. (2014). Crosstalk between TGF-β1 and complement activation augments epithelial injury in pulmonary fibrosis. FASEB Journal, 28(10), 4223-4234. https://doi.org/10.1096/fj.13-247650