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EP(2) and EP(4) receptors on muscularis resident macrophages mediate LPS-induced intestinal dysmotility via iNOS upregulation through cAMP/ERK signals
Intestinal resident macrophages play an important role in gastrointestinal dysmotility by producing prostaglandins (PGs) and nitric oxide (NO) in inflammatory conditions. The causal correlation between PGs and NO in gastrointestinal inflammation has not been elucidated. In this study, we examined th...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Physiological Society
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3311437/ https://www.ncbi.nlm.nih.gov/pubmed/22159280 http://dx.doi.org/10.1152/ajpgi.00264.2011 |
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author | Tajima, Tsuyoshi Murata, Takahisa Aritake, Kosuke Urade, Yoshihiro Michishita, Masaki Matsuoka, Toshiyuki Narumiya, Shuh Ozaki, Hiroshi Hori, Masatoshi |
author_facet | Tajima, Tsuyoshi Murata, Takahisa Aritake, Kosuke Urade, Yoshihiro Michishita, Masaki Matsuoka, Toshiyuki Narumiya, Shuh Ozaki, Hiroshi Hori, Masatoshi |
author_sort | Tajima, Tsuyoshi |
collection | PubMed |
description | Intestinal resident macrophages play an important role in gastrointestinal dysmotility by producing prostaglandins (PGs) and nitric oxide (NO) in inflammatory conditions. The causal correlation between PGs and NO in gastrointestinal inflammation has not been elucidated. In this study, we examined the possible role of PGE(2) in the LPS-inducible inducible NO synthase (iNOS) gene expression in murine distal ileal tissue and macrophages. Treatment of ileal tissue with LPS increased the iNOS and cyclooxygenase (COX)-2 gene expression, which lead to intestinal dysmotility. However, LPS did not induce the expression of iNOS and COX-2 in tissue from macrophage colony-stimulating factor-deficient op/op mice, indicating that these genes are expressed in intestinal resident macrophages. iNOS and COX-2 protein were also expressed in dextran-phagocytized macrophages in the muscle layer. CAY10404, a COX-2 inhibitor, diminished LPS-dependent iNOS gene upregulation in wild-type mouse ileal tissue and also in RAW264.7 macrophages, indicating that PGs upregulate iNOS gene expression. EP(2) and EP(4) agonists upregulated iNOS gene expression in ileal tissue and isolated resident macrophages. iNOS mRNA induction mediated by LPS was decreased in the ileum isolated from EP(2) or EP(4) knockout mice. In addition, LPS failed to decrease the motility of EP(2) and EP(4) knockout mice ileum. EP(2)- or EP(4)-mediated iNOS expression was attenuated by KT-5720, a PKA inhibitor and PD-98059, an ERK inhibitor. Forskolin or dibutyryl-cAMP mimics upregulation of iNOS gene expression in macrophages. In conclusion, COX-2-derived PGE(2) induces iNOS expression through cAMP/ERK pathways by activating EP(2) and EP(4) receptors in muscularis macrophages. NO produced in muscularis macrophages induces dysmotility during gastrointestinal inflammation. |
format | Online Article Text |
id | pubmed-3311437 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | American Physiological Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-33114372012-03-28 EP(2) and EP(4) receptors on muscularis resident macrophages mediate LPS-induced intestinal dysmotility via iNOS upregulation through cAMP/ERK signals Tajima, Tsuyoshi Murata, Takahisa Aritake, Kosuke Urade, Yoshihiro Michishita, Masaki Matsuoka, Toshiyuki Narumiya, Shuh Ozaki, Hiroshi Hori, Masatoshi Am J Physiol Gastrointest Liver Physiol Inflammation/Immunity/Mediators Intestinal resident macrophages play an important role in gastrointestinal dysmotility by producing prostaglandins (PGs) and nitric oxide (NO) in inflammatory conditions. The causal correlation between PGs and NO in gastrointestinal inflammation has not been elucidated. In this study, we examined the possible role of PGE(2) in the LPS-inducible inducible NO synthase (iNOS) gene expression in murine distal ileal tissue and macrophages. Treatment of ileal tissue with LPS increased the iNOS and cyclooxygenase (COX)-2 gene expression, which lead to intestinal dysmotility. However, LPS did not induce the expression of iNOS and COX-2 in tissue from macrophage colony-stimulating factor-deficient op/op mice, indicating that these genes are expressed in intestinal resident macrophages. iNOS and COX-2 protein were also expressed in dextran-phagocytized macrophages in the muscle layer. CAY10404, a COX-2 inhibitor, diminished LPS-dependent iNOS gene upregulation in wild-type mouse ileal tissue and also in RAW264.7 macrophages, indicating that PGs upregulate iNOS gene expression. EP(2) and EP(4) agonists upregulated iNOS gene expression in ileal tissue and isolated resident macrophages. iNOS mRNA induction mediated by LPS was decreased in the ileum isolated from EP(2) or EP(4) knockout mice. In addition, LPS failed to decrease the motility of EP(2) and EP(4) knockout mice ileum. EP(2)- or EP(4)-mediated iNOS expression was attenuated by KT-5720, a PKA inhibitor and PD-98059, an ERK inhibitor. Forskolin or dibutyryl-cAMP mimics upregulation of iNOS gene expression in macrophages. In conclusion, COX-2-derived PGE(2) induces iNOS expression through cAMP/ERK pathways by activating EP(2) and EP(4) receptors in muscularis macrophages. NO produced in muscularis macrophages induces dysmotility during gastrointestinal inflammation. American Physiological Society 2012-03-01 2011-12-08 /pmc/articles/PMC3311437/ /pubmed/22159280 http://dx.doi.org/10.1152/ajpgi.00264.2011 Text en Copyright © 2012 the American Physiological Society This document may be redistributed and reused, subject to www.the-aps.org/publications/journals/funding_addendum_policy.htm (http://www.the-aps.org/publications/journals/funding_addendum_policy.htm) . |
spellingShingle | Inflammation/Immunity/Mediators Tajima, Tsuyoshi Murata, Takahisa Aritake, Kosuke Urade, Yoshihiro Michishita, Masaki Matsuoka, Toshiyuki Narumiya, Shuh Ozaki, Hiroshi Hori, Masatoshi EP(2) and EP(4) receptors on muscularis resident macrophages mediate LPS-induced intestinal dysmotility via iNOS upregulation through cAMP/ERK signals |
title | EP(2) and EP(4) receptors on muscularis resident macrophages mediate LPS-induced intestinal dysmotility via iNOS upregulation through cAMP/ERK signals |
title_full | EP(2) and EP(4) receptors on muscularis resident macrophages mediate LPS-induced intestinal dysmotility via iNOS upregulation through cAMP/ERK signals |
title_fullStr | EP(2) and EP(4) receptors on muscularis resident macrophages mediate LPS-induced intestinal dysmotility via iNOS upregulation through cAMP/ERK signals |
title_full_unstemmed | EP(2) and EP(4) receptors on muscularis resident macrophages mediate LPS-induced intestinal dysmotility via iNOS upregulation through cAMP/ERK signals |
title_short | EP(2) and EP(4) receptors on muscularis resident macrophages mediate LPS-induced intestinal dysmotility via iNOS upregulation through cAMP/ERK signals |
title_sort | ep(2) and ep(4) receptors on muscularis resident macrophages mediate lps-induced intestinal dysmotility via inos upregulation through camp/erk signals |
topic | Inflammation/Immunity/Mediators |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3311437/ https://www.ncbi.nlm.nih.gov/pubmed/22159280 http://dx.doi.org/10.1152/ajpgi.00264.2011 |
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