TGF-β2 Suppresses Macrophage Cytokine Production and Mucosal Inflammatory Responses in the Developing Intestine

被引：171

作者：

Maheshwari, Akhil ^{[1
,2
,3
,6
]}

Kelly, David R. ^{[2
]}

Nicola, Teodora ^{[1
]}

Ambalavanan, Namasivayam ^{[1
,2
,3
]}

Jain, Sunil K. ^{[7
]}

Murphy-Ullrich, Joanne ^{[2
,3
]}

Athar, Mohammad ^{[4
]}

Shimamura, Masako ^{[1
]}

Bhandari, Vineet ^{[8
]}

Aprahamian, Charles ^{[5
]}

Dimmitt, Reed A. ^{[1
,5
]}

Serra, Rosa ^{[2
,3
]}

Ohls, Robin K. ^{[9
]}

机构：

[1] Univ Alabama, Dept Pediat, Birmingham, AL USA

[2] Univ Alabama, Dept Cell Biol, Birmingham, AL 35294 USA

[3] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA

[4] Univ Alabama, Dept Dermatol, Birmingham, AL 35294 USA

[5] Univ Alabama, Dept Surg, Birmingham, AL 35294 USA

[6] Univ Illinois, Dept Pediat, Chicago, IL 60612 USA

[7] Univ Texas Med Branch, Dept Pediat, Galveston, TX 77550 USA

[8] Yale Univ, Dept Pediat, New Haven, CT 06520 USA

[9] Univ New Mexico, Dept Pediat, Albuquerque, NM 87131 USA

来源：

GASTROENTEROLOGY | 2011年 / 140卷 / 01期

基金：

美国国家卫生研究院;

关键词：

Necrotizing Enterocolitis; Macrophage; Newborn; Inflammation; TGF-beta; GROWTH-FACTOR-BETA; TGF-BETA; NECROTIZING ENTEROCOLITIS; ENDOTOXIN-TOLERANCE; EPITHELIAL-CELLS; CROHNS-DISEASE; EXPRESSION; COLITIS; RECEPTOR; EMBRYOGENESIS;

D O I：

10.1053/j.gastro.2010.09.043

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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-beta (TGF-beta) 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-beta 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-beta, particularly the TGF-beta(2) isoform. NEC was associated with decreased tissue expression of TGF-beta(2) and decreased TGF-beta bioactivity. In mice, disruption of TGF-beta signaling worsened NEC-like inflammatory mucosal injury, whereas enteral supplementation with recombinant TGF-beta(2) was protective. CONCLUSIONS: Intestinal macrophages progressively acquire a noninflammatory profile during gestational development. TGF-beta, particularly the TGF-beta(2) isoform, suppresses macrophage inflammatory responses in the developing intestine and protects against inflammatory mucosal injury. Enterally administered TGF-beta(2) protected mice from experimental NEC-like injury.

引用

页码：242 / 253

页数：12

共 44 条

[1] FGF-10 is decreased in bronchopulmonary dysplasia and suppressed by Toll-like receptor activation [J].