IL-1beta inhibits intestinal smooth muscle proliferation in an organ culture system: involvement of COX-2 and iNOS induction in muscularis resident macrophages.
Intestinal inflammation causes hyperplasia of smooth muscle that leads to thickening of the smooth muscle layer, resulting in dysmotility. IL-1beta is a proinflammatory cytokine that plays a central role in intestinal inflammation. In this study, to evaluate the effect of IL-1beta on proliferation of ileal smooth muscle cells in vivo, we utilized an organ culture system. When rat ileal smooth muscle tissue was cultured under serum-free conditions for 3 days, most smooth muscle cells maintained their arrangement and kept their contractile phenotype. When 10% FBS was added, an increased number of smooth muscle cells per unit area was observed. Moreover, immunohistochemical staining for PCNA demonstrated that FBS induced proliferation of smooth muscle cells. IL-1beta inhibited the proliferative effect of FBS. Furthermore, IL-1beta upregulated inducible nitric oxide (NO) synthase and cyclooxygenase-2 mRNA and protein and thus stimulated NO and PGE(2) productions. Moreover, exogenously applied NO and PGE(2) inhibited the increase of bromodeoxyuridine-positive cells stimulated with FBS. Immunostaining revealed that the majority of cyclooxygenase-2 and inducible NO synthase was located in the dense network of macrophages resident in the muscularis, which were immunoreactive to ED2. Based on these findings, IL-1beta acts as an anti-proliferative mediator, which acts indirectly through the production of PGE(2) and NO from resident macrophage within ileal smooth muscle tissue.
Ohama
Takashi
T
Dept. of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The Univ. of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan.
Hori
Masatoshi
M
Momotani
Eiichi
E
Elorza
Margaret
M
Gerthoffer
William T
WT
Ozaki
Hiroshi
H
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016895:Culture Media, Serum-Free; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004790:Enzyme Induction; D007082:Ileum / Q000166:cytology / Q000187:drug effects; D053583:Interleukin-1beta / Q000494:pharmacology*; D008264:Macrophages / Q000502:physiology; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D009924:Organ Culture Techniques; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D016895:Culture Media, Serum-Free; D053583:Interleukin-1beta; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat