EP2 and EP4 Receptors on Muscularis Resident Macrophages Mediate LPS-induced Intestinal Dysmotility Via INOS Upregulation Through CAMP/ERK Signals

Overview

Journal Am J Physiol Gastrointest Liver Physiol

Publisher American Physiological Society

Specialties Gastroenterology
Physiology

Date 2011 Dec 14

PMID 22159280

Citations 23

Authors

Tsuyoshi Tajima

Takahisa Murata

Kosuke Aritake

Yoshihiro Urade

Masaki Michishita

Toshiyuki Matsuoka

Shuh Narumiya

Hiroshi Ozaki

Masatoshi Hori

Affiliations

Soon will be listed here.

Abstract

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.

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References

Schwarz N, Kalff J, Turler A, Engel B, Watkins S, Billiar T . Prostanoid production via COX-2 as a causative mechanism of rodent postoperative ileus. Gastroenterology. 2001; 121(6):1354-71. DOI: 10.1053/gast.2001.29605. View

De Winter B, Bredenoord A, De Man J, Moreels T, Herman A, Pelckmans P . Effect of inhibition of inducible nitric oxide synthase and guanylyl cyclase on endotoxin-induced delay in gastric emptying and intestinal transit in mice. Shock. 2002; 18(2):125-31. DOI: 10.1097/00024382-200208000-00006. View

Suzuki T, Won K, Horiguchi K, Kinoshita K, Hori M, Torihashi S . Muscularis inflammation and the loss of interstitial cells of Cajal in the endothelin ETB receptor null rat. Am J Physiol Gastrointest Liver Physiol. 2004; 287(3):G638-46. DOI: 10.1152/ajpgi.00077.2004. View

Ozaki H, Kawai T, Shuttleworth C, Won K, Suzuki T, Sato K . Isolation and characterization of resident macrophages from the smooth muscle layers of murine small intestine. Neurogastroenterol Motil. 2004; 16(1):39-51. DOI: 10.1046/j.1365-2982.2003.00461.x. View

Kalff J, Carlos T, Schraut W, Billiar T, Simmons R, Bauer A . Surgically induced leukocytic infiltrates within the rat intestinal muscularis mediate postoperative ileus. Gastroenterology. 1999; 117(2):378-87. DOI: 10.1053/gast.1999.0029900378. View

Hizaki H, Segi E, Sugimoto Y, Hirose M, Saji T, Ushikubi F . Abortive expansion of the cumulus and impaired fertility in mice lacking the prostaglandin E receptor subtype EP(2). Proc Natl Acad Sci U S A. 1999; 96(18):10501-6. PMC: 17918. DOI: 10.1073/pnas.96.18.10501. View

Sugimoto Y, Narumiya S . Prostaglandin E receptors. J Biol Chem. 2007; 282(16):11613-7. DOI: 10.1074/jbc.R600038200. View

Fujino H, West K, Regan J . Phosphorylation of glycogen synthase kinase-3 and stimulation of T-cell factor signaling following activation of EP2 and EP4 prostanoid receptors by prostaglandin E2. J Biol Chem. 2001; 277(4):2614-9. DOI: 10.1074/jbc.M109440200. View

Kaisho T, Akira S . Toll-like receptor function and signaling. J Allergy Clin Immunol. 2006; 117(5):979-87. DOI: 10.1016/j.jaci.2006.02.023. View

10.

Mikkelsen H, Rumessen J . Characterization of macrophage-like cells in the external layers of human small and large intestine. Cell Tissue Res. 1992; 270(2):273-9. DOI: 10.1007/BF00328013. View

11.

Timoshenko A, Lala P, Chakraborty C . PGE2-mediated upregulation of iNOS in murine breast cancer cells through the activation of EP4 receptors. Int J Cancer. 2003; 108(3):384-9. DOI: 10.1002/ijc.11575. View

12.

Mikkelsen H, Thuneberg L . Op/op mice defective in production of functional colony-stimulating factor-1 lack macrophages in muscularis externa of the small intestine. Cell Tissue Res. 1999; 295(3):485-93. DOI: 10.1007/s004410051254. View

13.

Takada Y, Hisamatsu T, Kamada N, Kitazume M, Honda H, Oshima Y . Monocyte chemoattractant protein-1 contributes to gut homeostasis and intestinal inflammation by composition of IL-10-producing regulatory macrophage subset. J Immunol. 2010; 184(5):2671-6. DOI: 10.4049/jimmunol.0804012. View

14.

Bjarnason I, Zanelli G, Smith T, Prouse P, Williams P, Smethurst P . Nonsteroidal antiinflammatory drug-induced intestinal inflammation in humans. Gastroenterology. 1987; 93(3):480-9. DOI: 10.1016/0016-5085(87)90909-7. View

15.

Narumiya S . Prostanoids in immunity: roles revealed by mice deficient in their receptors. Life Sci. 2003; 74(2-3):391-5. DOI: 10.1016/j.lfs.2003.09.025. View

16.

Kawai T, Akira S . Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med. 2007; 13(11):460-9. DOI: 10.1016/j.molmed.2007.09.002. View

17.

Hori M, Nobe H, Horiguchi K, Ozaki H . MCP-1 targeting inhibits muscularis macrophage recruitment and intestinal smooth muscle dysfunction in colonic inflammation. Am J Physiol Cell Physiol. 2007; 294(2):C391-401. DOI: 10.1152/ajpcell.00056.2007. View

18.

Turler A, Kalff J, Moore B, Hoffman R, Billiar T, Simmons R . Leukocyte-derived inducible nitric oxide synthase mediates murine postoperative ileus. Ann Surg. 2006; 244(2):220-9. PMC: 1602158. DOI: 10.1097/01.sla.0000229963.37544.59. View

19.

Kunikata T, Tanaka A, Miyazawa T, Kato S, Takeuchi K . 16,16-Dimethyl prostaglandin E2 inhibits indomethacin-induced small intestinal lesions through EP3 and EP4 receptors. Dig Dis Sci. 2002; 47(4):894-904. DOI: 10.1023/a:1014725024519. View

20.

Ohama T, Hori M, Ozaki H . Mechanism of abnormal intestinal motility in inflammatory bowel disease: how smooth muscle contraction is reduced?. J Smooth Muscle Res. 2007; 43(2):43-54. DOI: 10.1540/jsmr.43.43. View