Role of STAT6 and mast cells in IL-4- and IL-13-induced alterations in murine intestinal epithelial cell function.
Gastrointestinal nematode infections generally invoke a type 2 cytokine response, characterized by the production of IL-4, IL-5, IL-9, and IL-13. Among these cytokines, IL-4 and IL-13 exhibit a functional overlap that can be explained by the sharing of a common receptor or receptor component (IL-4Ralpha). Binding of IL-4 by either the type 1 or 2 IL-4R, or of IL-13 by the type 2 IL-4R, initiates Jak-dependent tyrosine phosphorylation of the IL-4Ralpha-chain and the transcription factor, STAT6. In the present study, we investigated: 1) whether IL-13 has effects on intestinal epithelial cells similar to those observed with IL-4, and 2) whether the effects of IL-4 and IL-13 depend on STAT6 signaling and/or mast cells. BALB/c, STAT6(-/-), and mast cell-deficient W/W(v) mice or their +/+ littermates were treated with a long-lasting formulation of recombinant mouse IL-4 (IL-4C) or with IL-13 for seven days. Segments of jejunum were mounted in Ussing chambers to measure mucosal permeability; chloride secretion in response to PGE(2), histamine, 5-hydroxytryptamine, or acetylcholine; and Na(+)-linked glucose absorption. IL-4C and IL-13 increased mucosal permeability, decreased glucose absorption, and decreased chloride secretion in response to 5-hydroxytryptamine. These effects were dependent on STAT6 signaling. Responses to PGE(2) and histamine, which were dependent on mast cells and STAT6, were enhanced by IL-4C, but not by IL-13. The effects of IL-4 and IL-13 on intestinal epithelial cell function may play a critical role in host protection against gastrointestinal nematodes.
Madden
Kathleen B
KB
Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Whitman
Lucia
L
Sullivan
Carolyn
C
Gause
William C
WC
Urban
Joseph F
JF
Katona
Ildy M
IM
Finkelman
Fred D
FD
Shea-Donohue
Terez
T
D000818:Animals; D002452:Cell Count; D016207:Cytokines / Q000494:pharmacology; D015232:Dinoprostone / Q000502:physiology; D005260:Female; D006632:Histamine / Q000494:pharmacology; D007113:Immunity, Innate / Q000235:genetics; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D050800:STAT6 Transcription Factor; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D016207:Cytokines; D018793:Interleukin-13; D050800:STAT6 Transcription Factor; D012702:Serotonin Antagonists; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D012701:Serotonin; D006632:Histamine; D015232:Dinoprostone