TGF-β2 suppresses macrophage cytokine production and mucosal inflammatory responses in the developing intestine

Akhil Maheshwari, David R. Kelly, Teodora Nicola, Namasivayam Ambalavanan, Sunil K. Jain, Joanne Murphyullrich, Mohammad Athar, Masako Shimamura, Vineet Bhandari, Charles Aprahamian, Reed A. Dimmitt, Rosa Serra, Robin K. Ohls

Research output: Contribution to journalArticle

114 Scopus citations

Abstract

Background & Aims: Premature neonates are predisposed to necrotizing enterocolitis (NEC), an idiopathic, inflammatory bowel necrosis. We investigated whether NEC occurs in the preterm intestine due to incomplete noninflammatory differentiation of intestinal macrophages, which increases the risk of a severe mucosal inflammatory response to bacterial products. Methods: We compared inflammatory properties of human/murine fetal, neonatal, and adult intestinal macrophages. To investigate gut-specific macrophage differentiation, we next treated monocyte-derived macrophages with conditioned media from explanted human fetal and adult intestinal tissues. Transforming growth factor-β (TGF-β) expression and bioactivity were measured in fetal/adult intestine and in NEC. Finally, we used wild-type and transgenic mice to investigate the effects of deficient TGF-β signaling on NEC-like inflammatory mucosal injury. Results: Intestinal macrophages in the human preterm intestine (fetus/premature neonate), but not in full-term neonates and adults, expressed inflammatory cytokines. Macrophage cytokine production was suppressed in the developing intestine by TGF-β, particularly the TGF-β2 isoform. NEC was associated with decreased tissue expression of TGF-β2 and decreased TGF-β bioactivity. In mice, disruption of TGF-β signaling worsened NEC-like inflammatory mucosal injury, whereas enteral supplementation with recombinant TGF-β2 was protective. Conclusions:: Intestinal macrophages progressively acquire a noninflammatory profile during gestational development. TGF-β, particularly the TGF-β2 isoform, suppresses macrophage inflammatory responses in the developing intestine and protects against inflammatory mucosal injury. Enterally administered TGF-β2 protected mice from experimental NEC-like injury.

Original languageEnglish (US)
Pages (from-to)242-253
Number of pages12
JournalGastroenterology
Volume140
Issue number1
DOIs
StatePublished - Jan 2011

Keywords

  • Inflammation
  • Macrophage
  • Necrotizing Enterocolitis
  • Newborn
  • TGF-β

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Maheshwari, A., Kelly, D. R., Nicola, T., Ambalavanan, N., Jain, S. K., Murphyullrich, J., Athar, M., Shimamura, M., Bhandari, V., Aprahamian, C., Dimmitt, R. A., Serra, R., & Ohls, R. K. (2011). TGF-β2 suppresses macrophage cytokine production and mucosal inflammatory responses in the developing intestine. Gastroenterology, 140(1), 242-253. https://doi.org/10.1053/j.gastro.2010.09.043