Role of IL-4, IL-13, and STAT6 in inflammation-induced hypercontractility of murine smooth muscle cells.
T helper 2 (Th2) cytokines interleukin (IL)-4 and IL-13, which activate signal transducer and activator of transcription 6 (STAT6) are expressed in the muscularis externa during nematode infection and are candidate mediators of the associated hypercontractility. To determine the locus of action of these cytokines, we examined the IL-4- and IL-13-induced hypercontractility of the isolated muscle cells from STAT6 +/+ and STAT6 -/- mice. We compared the results with cells isolated from Trichinella spiralis-infected STAT6 +/+ and STAT6 -/- mice. Carbamylcholine chloride (Carbachol) induced the contraction of jejunal muscle cells in a concentration-dependent manner maximal contraction (R(max) 26.7 +/- 1.9%). Cells from T. spiralis-infected STAT6 -/- mice showed the hypertrophy (cell lengths 41.4 +/- 0.8 to 89.0 +/- 8.7 microm) and hypercontractility (R(max) 37.5 +/- 1.3%) induced by infection. IL-4Ralpha mRNA was detected in dispersed smooth muscle cells. Incubation of longitudinal muscle-myenteric plexus (LMMP) with IL-4 and IL-13 enhanced Carbachol-induced muscle contraction (R(max) 35.5 +/- 1.9 and 32.4 +/- 2.9%, respectively). Incubation of LMMP from STAT6 -/- mice with IL-4 did not enhance the contraction. The hypercontractility in T. spiralis-infected mice was attenuated in STAT6 -/- mice (P < 0.02). These results indicate both IL-4 and IL-13 induce hypercontractility of muscle cells via the STAT6 pathway, and this is the basis for hypercontractility observed in T. spiralis-infected mice.
Akiho
Hirotada
H
Intestinal Diseases Research Program, Department of Medicine, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N3Z5, Canada.
Blennerhassett
Patricia
P
Deng
Yikang
Y
Collins
Stephen M
SM
D000818:Animals; D017252:CD3 Complex / Q000032:analysis; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005769:Gastrointestinal Motility / Q000276:immunology*; D015870:Gene Expression / Q000276:immunology; D018793:Interleukin-13 / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology*; D007422:Intestines / Q000276:immunology / Q000469:parasitology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects / Q000276:immunology; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D009130:Muscle, Smooth / Q000166:cytology / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D019948:Receptors, Interleukin-4 / Q000235:genetics; D050800:STAT6 Transcription Factor; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D015534:Trans-Activators / Q000276:immunology*; D017160:Trichinella spiralis; D014235:Trichinellosis / Q000276:immunology / Q000503:physiopathology
D017252:CD3 Complex; D018679:Cholinergic Agonists; D018793:Interleukin-13; D012333:RNA, Messenger; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D002217:Carbachol