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

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posted on 2011-03-01, 00:00 authored by Akhil Maheshwari, David R. Kelly, Teodora Nicola, Namasivayam Ambalavanan, Sunil K. Jain, Joanne Murphy-Ullrich, Mohammad Athar, Masako Shimamura, Vineet Bhandari, Charles Aprahamian, Reed A. Dimmitt, Rosa Serra, Robin K. Ohls
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-β(2) isoform. NEC was associated with decreased tissue expression of TGF-β(2) and decreased TGF-β bioactivity. In mice, disruption of TGF-β signaling worsened NEC-like inflammatory mucosal injury, whereas enteral supplementation with recombinant TGF-β(2) was protective. CONCLUSIONS: Intestinal macrophages progressively acquire a noninflammatory profile during gestational development. TGF-β, particularly the TGF-β(2) isoform, suppresses macrophage inflammatory responses in the developing intestine and protects against inflammatory mucosal injury. Enterally administered TGF-β(2) protected mice from experimental NEC-like injury.

Funding

Supported by the NIH awards HD059142, HD043397, American Gastroenterological Association 2006 Research Scholar Award, and a research grant from the CACA Jones Family Foundation (A.M.), NIH grants HD046513, HL092906, ATS PH-06-006 (N.A.), and ES015323 (M.A.). Blood monocytes and adult jejunal tissue were received from Core 2 of the UAB Mucosal Immunology and HIV Center (DK64400). The work was made possible in part by the Research Facilities Improvement Grant C06RR15490 from the National Center for Research Resources.

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Publisher Statement

Post print version of article may differ from published version. The definitive version is available through Elsevier at DOI: 10.1053/j.gastro.2010.09.043

Publisher

Elsevier

Language

  • en_US

issn

1528-0012

Issue date

2011-01-01

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