Immune-mediated signaling in intestinal goblet cells via PI3-kinase- and AKT-dependent pathways.
In the intestinal epithelium, activation of phosphatidylinositol 3-kinase (PI3-kinase)/AKT pathways, via growth factor-mediated signaling, has been shown to regulate cell proliferation and inhibit apoptosis. An immune-activated receptor critical for Th2 immune responses, IL-4Ralpha can also activate PI3-kinase via insulin receptor substrate (IRS)-dependent signaling. Here, using the intestinal goblet cell-specific gene RELMbeta, we investigated the effect of PI3-kinase activation via Th2 immune responses on the goblet cell phenotype. IL-13 stimulation activated PI3-kinase and AKT signal transduction in LS174T cells. Not only did pharmacological inhibition of PI3-kinase and AKT1/2 inhibit RELMbeta induction by IL-13, but AKT inhibition also significantly reduced constitutive basal expression of RELMbeta, a response reproduced by the simultaneous pharmacological inhibition of both epidermal growth factor receptor and IGF-I receptor signaling. In vivo, the disruption of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), an inhibitor of PI3-kinase activation, led to the activation of RELMbeta expression in the small intestine. Furthermore, induction of an intestinal Th2 immune response by infection with a small intestinal nematode parasite, Heligmosomoides polygyrus, led to enhanced epithelial cell proliferation, activation of AKT as demonstrated by the loss of Foxo1 nuclear localization, and robust induction of RELMbeta expression in wild-type, but not IL-4Ralpha knockout, mice. These results demonstrate that Th2 immune responses can regulate goblet cell responses by activation of PI3-kinase and AKT pathways via IL-4Ralpha.
Wang
Mei-Lun
ML
Div. of Gastroenterology, Univ. of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Keilbaugh
Sue A
SA
Cash-Mason
Tanesha
T
He
Xi C
XC
Li
Linheng
L
Wu
Gary D
GD
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D020397:Goblet Cells / Q000378:metabolism*; D006729:Hormones, Ectopic; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000473:pathology; D007421:Intestine, Small / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009349:Nematode Infections / Q000276:immunology; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D018418:Th2 Cells / Q000502:physiology; D053662:Interleukin-4 Receptor alpha Subunit
D006729:Hormones, Ectopic; D055504:Insulin Receptor Substrate Proteins; D036341:Intercellular Signaling Peptides and Proteins; D018793:Interleukin-13; D015847:Interleukin-4; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C526297:IRS2 protein, human; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C486522:Retnlb protein, mouse