title: IL-33-induced alterations in murine intestinal function and cytokine responses are MyD88, STAT6, and IL-13 dependent.
abstract: IL-33 is a recently identified cytokine member of the IL-1 family. The biological activities of IL-33 are associated with promotion of Th2 and inhibition of Th1/Th17 immune responses. Exogenous IL-33 induces a typical "type 2" immune response in the gastrointestinal tract, yet the underlying mechanisms remain to be fully elucidated. In addition, the role of IL-33 in the regulation of gastrointestinal function is not known. The present study investigated IL-33-dependent intestinal immunity and function in mice. Exogenous IL-33 induced a polarized type 2 cytokine response in the intestine that was entirely MyD88 dependent but STAT6 and IL-13 independent. Mice injected with recombinant IL-33 exhibited intestinal smooth muscle hypercontractility, decreased epithelial responses to acetylcholine and glucose, and increased mucosal permeability. IL-33 effects on intestinal epithelial function were STAT6 dependent, and both IL-4 and IL-13 appeared to play a role. The effects on smooth muscle function, however, were attributable to both STAT6-dependent and -independent mechanisms. In addition, IL-13 induction of insulin-like growth factor-1 was implicated in IL-33-induced smooth muscle hypertrophy. Finally, alternative activation of macrophages induced by IL-33 revealed a novel pathway that is IL-4, IL-13, and STAT6 independent. Thus manipulating IL-33 or related signaling pathways represents a potential therapeutic strategy for treating inflammatory diseases associated with dysregulated intestinal function.
authors.affiliation: Department of Medicine and the Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Zhonghan
authors.initials: Z
authors.lastname: Yang
authors.forename: Rex
authors.initials: R
authors.lastname: Sun
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Grinchuk
authors.forename: Joan Antoni
authors.initials: JA
authors.lastname: Fernández-Blanco
authors.forename: Joan Antoni Fernandez
authors.initials: JA
authors.lastname: Blanco
authors.forename: Luigi
authors.initials: L
authors.lastname: Notari
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Bohl
authors.forename: Leon P
authors.initials: LP
authors.lastname: McLean
authors.forename: Thirumalai R
authors.initials: TR
authors.lastname: Ramalingam
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wynn
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Urban
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
authors.forename: Terez
authors.initials: T
authors.lastname: Shea-Donohue
authors.forename: Aiping
authors.initials: A
authors.lastname: Zhao
mesh_terms: D000818:Animals; D004848:Epithelium / Q000276:immunology; D006965:Hyperplasia / Q000139:chemically induced; D018793:Interleukin-13 / Q000502:physiology*; D000067596:Interleukin-33; D007378:Interleukins / Q000502:physiology*; D007422:Intestines / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D050800:STAT6 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C506535:Il33 protein, mouse; D018793:Interleukin-13; D000067596:Interleukin-33; D007378:Interleukins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse