Gastroenterology

Gastroenterology

Volume 140, Issue 1, January 2011, Pages 242-253
Gastroenterology

Basic—Alimentary Tract
TGF-β2 Suppresses Macrophage Cytokine Production and Mucosal Inflammatory Responses in the Developing Intestine

https://doi.org/10.1053/j.gastro.2010.09.043Get rights and content

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.

Section snippets

Human Intestinal Tissue Samples

Human intestinal tissues were collected after approval by local Institutional Review Boards. Fetal intestinal tissue (11−24 weeks, n = 25) was obtained at elective terminations of pregnancy. Tissue samples of advanced NEC (n = 8) were compared with healthy tissue margins obtained during resection for indications other than NEC (premature neonates: repair of ostomy, n = 5; gestational age 27, 27.5, 28.5, 30.5, and 32 weeks; full-term neonates: atresia/obstruction; n = 3). Adult tissues were

Macrophages in the Preterm Human Intestine Express Inflammatory Cytokines

To investigate our hypothesis that the inflammatory down-regulation of intestinal macrophages is a function of gestational maturation, we first compared macrophages in intestinal tissue samples from human fetuses, premature and full-term neonates, and adults by immunohistochemistry for inflammatory cytokines. Consistent with existing information,6, 25 macrophages in the full-term neonatal and adult intestine did not express TNF-α or IL-8/CXCL8. However, macrophages in preterm intestine (from

Discussion

We present a detailed investigation into the normal development of LPS tolerance in intestinal macrophages and a novel pathophysiological model for NEC with possible therapeutic implications. In contrast to the noninflammatory functional profile of intestinal macrophages seen in the mature host, macrophages in the preterm intestine can respond to bacterial products to produce a robust inflammatory response. In the normal fetus, intestinal macrophages undergo progressive inflammatory

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by the National Institutes of Health awards HD059142, HD043397, American Gastroenterological Association 2006 Research Scholar Award, and a research grant from the CACA Jones Family Foundation (A.M.), National Institutes of Health 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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