Molecular mechanism of interleukin-2-induced mucosal homeostasis

Jayshree Mishra, Christopher Waters, Narendra Kumar

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Sustained damage to the mucosal lining in patients with inflammatory bowel disease (IBD) facilitates translocation of intestinal microbes to submucosal immune cells leading to chronic inflammation. Previously, we demonstrated the role of Jak3 in IL-2-induced intestinal epithelial cell (IEC) migration, one of the early events during intestinal wound repair. In this study, we demonstrate that IL-2 also plays a role in IEC homeostasis through concentration-dependent regulation of IEC proliferation and cell death. At lower concentrations (≤50 U/ml), IL-2 promoted proliferation, while at higher concentrations (100 U/ml), it promoted apoptosis. Activation by IL-2 led to tyrosine phosphorylation-dependent interactions between Jak3 and p52ShcA only at lower concentrations. Phosphatase SHP1 dephosphorylated IL-2-induced phosphorylated p52ShcA. Higher concentrations of IL-2 decreased the phosphorylation of Jak3 and p52ShcA, disrupted their interactions, redistributed Jak3 to the nucleus, and induced apoptosis in IEC. IL-2 also induced dose-dependent upregulation of p52shcA and downregulation of jak3- mRNA. Constitutive overexpression and mir-shRNA-mediated knockdown studies showed that expression of both Jak3 and p52ShcA were necessary for IL-2-induced proliferation of IEC. Doxycyclineregulated sh-RNA expression demonstrated that IL-2-induced downregulation of jak3-mRNA was responsible for higher IL-2-induced apoptosis in IEC. Collectively, these data demonstrate a novel mechanism of IL-2-induced mucosal homeostasis through posttranslational and transcriptional regulation of Jak3 and p52ShcA.

Original languageEnglish (US)
Pages (from-to)735-747
Number of pages13
JournalAmerican Journal of Physiology - Cell Physiology
Volume302
Issue number5
DOIs
StatePublished - Mar 1 2012

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Interleukin-2
Homeostasis
Epithelial Cells
Apoptosis
Down-Regulation
Non-Receptor Type 6 Protein Tyrosine Phosphatase
Phosphorylation
Messenger RNA
Inflammatory Bowel Diseases
Small Interfering RNA
Cell Movement
Tyrosine
Cell Death
Up-Regulation
Cell Proliferation
RNA
Inflammation
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Cell Biology
  • Physiology

Cite this

Molecular mechanism of interleukin-2-induced mucosal homeostasis. / Mishra, Jayshree; Waters, Christopher; Kumar, Narendra.

In: American Journal of Physiology - Cell Physiology, Vol. 302, No. 5, 01.03.2012, p. 735-747.

Research output: Contribution to journalArticle

Mishra, Jayshree ; Waters, Christopher ; Kumar, Narendra. / Molecular mechanism of interleukin-2-induced mucosal homeostasis. In: American Journal of Physiology - Cell Physiology. 2012 ; Vol. 302, No. 5. pp. 735-747.
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