Ontogeny of the mucosal immune response

MacDonald, Thomas T.; Spencer, Jo

doi:10.1007/bf00197501

Cited by 15 publications

(13 citation statements)

References 20 publications

(22 reference statements)

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“…This interaction leads to specific activation of transcription factors, such as NF-B, leading to production of proinflammatory cytokines (TNF-␣, IL-6, and IL-8) (8,23,28). IL-8 is a neutrophil-attracting chemokine known to be produced by enterocytes in response to inflammatory stimuli and plays an important role in recruiting neutrophils from the intravascular space to interstitial and luminal sites (4,19). NEC is characterized by a hemorrhagic inflammatory necrosis of the distal small bowel and proximal colon with extensive infiltration by neutrophils (5,17).…”

Section: Discussionmentioning

confidence: 99%

“…To confirm any differences in proinflammatory stimuli, we compared the endotoxin/IL-1␤ response in human small intestinal biopsies and in developing ileal xenografts. Organ culture was performed in a Falcon organ culture dish maintained at 37°C with 95% O 2-5% CO2 and saturated water vapor as described previously (19,23). Culture medium used was CMRL 1066 supplemented with glucose (5 g/l), tricine buffer (20 mol, pH 7.4), hydrocortisone hemisuccinate (0.5 g/l), b-retinyl acetate (1 mg/l), glutamine (3 mM), and 5% FBS (Hyclone, Logan, UT), penicillin G (100 U/l), and gentamicin (50 mg/l).…”

Section: Methodsmentioning

confidence: 99%

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Glucocorticoid responsiveness in developing human intestine: possible role in prevention of necrotizing enterocolitis

Nanthakumar

Young²,

Ko³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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Necrotizing enterocolitis (NEC) is a major inflammatory disease of the premature human intestine that can be prevented by glucocorticoids if given prenatally before the 34th wk of gestation. This observation suggests that a finite period of steroid responsiveness exists as has been demonstrated in animal models. Human intestinal xenografts were used to determine whether a glucocorticoid responsive period exists in the developing human intestine. Developmental responsiveness was measured by lactase activity and inflammatory responsiveness by IL-8, IL-6, and monocyte chemotactic protein-1 (MCP-1) induction after an endogenous (IL-1 beta) or exogenous (LPS) proinflammatory stimulus, respectively. Functional development of ileal xenografts were monitored for 30 wk posttransplantation, and the lactase activity recapitulated that predicted by in utero development. Cortisone acetate accelerated the ontogeny of lactase at 20 wk (immature) but the effect was lost by 30 wk (mature) posttransplant. Concomitant with accelerated maturation, the IL-8 response to both IL-1 beta and LPS was significantly dampened (from 6- to 3-fold) by glucocorticoid pretreatment in the immature but not mature xenografts. The induction of IL-8 was reflected at the level of IL-8 mRNA, suggesting transcriptional regulation. The excessive activation of IL-8 in the immature gut was mediated by a prolonged activation of ERK and p38 kinases and nuclear translocation of NF-kappa B due to low levels of I kappa B. Steroid pretreatment in immature intestine dampens activation of all three signaling pathways in response to proinflammatory stimuli. Therefore, accelerating intestinal maturation by glucocorticoids within the responsive period by accelerating functional and inflammatory maturation may provide an effective preventive therapy for NEC.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Glucocorticoid responsiveness in developing human intestine: possible role in prevention of necrotizing enterocolitis

Nanthakumar

Young²,

Ko³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Although age-related differences in cytokine/chemokine expression can account for these findings, maturational differences in the development of gut leukocyte populations are also likely to play an important role in the relative composition of leukocyte infiltrates during inflammatory injury. Macrophages are the first leukocytes to appear in the developing intestine, and the intestinal macrophage pool approaches mature levels in both its size and function by midgestation (2,22,26). In contrast, gut lymphocyte populations appear during fetal development a few weeks after macrophages but remain limited in size and repertoire until postnatal bacterial colonization and weaning (19,22,40).…”

Section: Tnbs-induced Gut Mucosal Injury In Pups Is Associated With Imentioning

confidence: 95%

Gut mucosal injury in neonates is marked by macrophage infiltration in contrast to pleomorphic infiltrates in adult: evidence from an animal model

MohanKumar¹,

Kaza

Jagadeeswaran³

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

100

118

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Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis of premature infants. In tissue samples of NEC, we identified numerous macrophages and a few neutrophils but not many lymphocytes. We hypothesized that these pathoanatomic characteristics of NEC represent a common tissue injury response of the gastrointestinal tract to a variety of insults at a specific stage of gut development. To evaluate developmental changes in mucosal inflammatory response, we used trinitrobenzene sulfonic acid (TNBS)-induced inflammation as a nonspecific insult and compared mucosal injury in newborn vs. adult mice. Enterocolitis was induced in 10-day-old pups and adult mice (n = 25 animals per group) by administering TNBS by gavage and enema. Leukocyte populations were enumerated in human NEC and in murine TNBS-enterocolitis using quantitative immunofluorescence. Chemokine expression was measured using quantitative polymerase chain reaction, immunoblots, and immunohistochemistry. Macrophage recruitment was investigated ex vivo using intestinal tissue-conditioned media and bone marrow-derived macrophages in a microchemotaxis assay. Similar to human NEC, TNBS enterocolitis in pups was marked by a macrophage-rich leukocyte infiltrate in affected tissue. In contrast, TNBS-enterocolitis in adult mice was associated with pleomorphic leukocyte infiltrates. Macrophage precursors were recruited to murine neonatal gastrointestinal tract by the chemokine CXCL5, a known chemoattractant for myeloid cells. We also demonstrated increased expression of CXCL5 in surgically resected tissue samples of human NEC, indicating that a similar pathway was active in NEC. We concluded that gut mucosal injury in the murine neonate is marked by a macrophage-rich leukocyte infiltrate, which contrasts with the pleomorphic leukocyte infiltrates in adult mice. In murine neonatal enterocolitis, macrophages were recruited to the inflamed gut mucosa by the chemokine CXCL5, indicating that CXCL5 and its cognate receptor CXCR2 merit further investigation as potential therapeutic targets in NEC.

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“…Macrophages first appear in the developing intestine at 11-12 wk of gestation, increase rapidly during the 12-to 22-wk period, and then continue to expand at a slower pace through early childhood (7,20,32,36,50,57). Intestinal macrophages play a critical host defense role in being the first phagocytic cells of the innate immune system to encounter luminal bacteria that breach the epithelium and gain access to the lamina propria (54,55).…”

mentioning

confidence: 97%

“…Similarly, TGF-␤ bioactivity is low in the early-and midgestation fetal intestine (A. Maheshwari, N. Ambalavanan, T. Nicola, D. R. Kelly, J. M. Murphy-Ullrich, M. Athar, M. Shimamura, V. Bhandari, C. Aprahamian, R. A. Dimmitt, R. Serra, and R. K. Ohls, unpublished observations). Finally, macrophages appear in the fetal intestine at least a few weeks before lymphocytes or neutrophils (7,32,36), suggesting that macrophage precursors are likely to be recruited to the early fetal intestine by chemoattractant(s) more specific for macrophage precursors than IL-8/CXCL8, which recruits both neutrophils and macrophage precursors (14,54), or TGF-␤, which mobilizes macrophage precursors as well as T lymphocytes (1,54).…”

mentioning

confidence: 98%

Epithelial cells in fetal intestine produce chemerin to recruit macrophages

Maheshwari

Kurundkar

Shaik

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Macrophages are first seen in the fetal intestine at 11-12 wk and rapidly increase in number during the 12- to 22-wk period of gestation. The development of macrophage populations in the fetal intestine precedes the appearance of lymphocytes and neutrophils and does not require the presence of dietary or microbial antigens. In this study, we investigated the role of chemerin, a recently discovered, relatively selective chemoattractant for macrophages, in the recruitment of macrophage precursors to the fetal intestine. Chemerin mRNA/protein expression was measured in jejunoileal tissue from 10- to 24-wk human fetuses, neonates operated for intestinal obstruction, and adults undergoing bariatric surgery. The expression of chemerin in intestinal epithelial cells (IECs) was confirmed by using cultured primary IECs and IEC-like cell lines in vitro. The regulatory mechanisms involved in chemerin expression were investigated by in silico and immunolocalization techniques. IECs in the fetal, but not mature, intestine express chemerin. Chemerin expression peaked in the fetal intestine at 20-24 wk and then decreased to original low levels by full term. During the 10- to 24-wk period, chemerin accounted for most of the macrophage chemotactic activity of cultured fetal IECs. The maturational changes in chemerin expression correlated with the expression of retinoic acid receptor-beta in the intestine. Chemerin is an important mediator of epithelial-macrophage cross talk in the fetal/premature, but not in the mature, intestine. Understanding the regulation of the gut macrophage pool is an important step in development of novel strategies to boost mucosal immunity in premature infants and other patient populations at risk of microbial translocation.

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Ontogeny of the mucosal immune response

Cited by 15 publications

References 20 publications

Glucocorticoid responsiveness in developing human intestine: possible role in prevention of necrotizing enterocolitis

Glucocorticoid responsiveness in developing human intestine: possible role in prevention of necrotizing enterocolitis

Gut mucosal injury in neonates is marked by macrophage infiltration in contrast to pleomorphic infiltrates in adult: evidence from an animal model

Epithelial cells in fetal intestine produce chemerin to recruit macrophages

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