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TGF-?2 suppresses macrophage cytokine production and mucosal inflammatory responses in the developing intestine.

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

SUBMITTER: Maheshwari A

PROVIDER: S-EPMC3008335 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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

Maheshwari Akhil A Kelly David R DR Nicola Teodora T Ambalavanan Namasivayam N Jain Sunil K SK Murphy-Ullrich Joanne J Athar Mohammad M Shimamura Masako M Bhandari Vineet V Aprahamian Charles C Dimmitt Reed A RA Serra Rosa R Ohls Robin K RK

Gastroenterology 20100924 1

<h4>Background & aims</h4>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.<h4>Methods</h4>We compared inflammatory properties of human/murine fetal, neonatal, and adult intestinal macrophages. To investigate ...[more]

PMID: 20875417

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Project description:Trichinella spiralis can modulate host immune responses to retain a suitable environment for its long-term survival. Incidentally, the parasite elicits regulatory effects through immunomodulatory molecule release, which can suppress host inflammation and may be used for the treatment of unrelated inflammatory diseases in someday. Here we identified and characterized a novel T. spiralis cystatin (TsCstN), which inhibits inflammation mediated by LPS-treated macrophages.Proteins contained in the excretory-secretory (ES) product of muscle-stage T. spiralis (ES-L1) were fractionated, and each was treated with mouse bone marrow-derived macrophages (mBMDMs) before LPS stimulation. The fractions that exhibited high immunomodulatory property by decreasing pro-inflammatory cytokines or increasing anti-inflammatory cytokines were identified by mass spectrometry. Incidentally, the conserved hypothetical protein (Tsp_04814) was selected for further characterization as it presented the most significant MS score. An annotation of Tsp_04814 using protein structural homology comparison suggested that it has high structural similarity to human cystatin E/M (TM score 0.690). The recombinant T. spiralis novel cystatin (rTsCstN) was expressed in Escherichia coli at a molecular weight of approximately 13 kDa. Mouse anti-rTsCstN polyclonal antibody (pAb) could detect native TsCstN in crude worm antigens (CWA) and ES-L1 and be predominantly localized in the stichosome and subcuticular cells. rTsCstN inhibited cysteine proteases in vitro, especially cathepsin L, at an optimal pH of 6. Besides, rTsCstN could be internalized into mBMDMs, which were mostly distributed in the cytoplasm and lysosome both before and after LPS stimulation. To evaluate the rTsCstN immunomodulatory properties on mBMDMs, rTsCstN was incubated with mBMDM before LPS stimulation; this demonstrated that rTsCstN suppressed pro-inflammatory cytokine production and MHC class II expression.T. spiralis L1-derived TsCstN was characterized as a novel cysteine protease inhibitor. The protein elicits an anti-inflammatory property by suppressing pro-inflammatory cytokines and interfering with the antigen presentation process through depletion of MHC class II expression.

Dataset Information

TGF-?2 suppresses macrophage cytokine production and mucosal inflammatory responses in the developing intestine.

Publications

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

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