Differential expression of transforming growth factors alpha and beta in rat intestinal epithelial cells.

Koyama, Shin-ya; Podolsky, Daniel K.

doi:10.1172/jci114080

Cited by 216 publications

(87 citation statements)

References 27 publications

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“…66,67 TGF-␤ transcripts have been documented in IEC-6 cells. 68 In the rat acetic acid gastric ulcer model, TGF-␤1 levels reached a peak after 2 days by immunohistochemistry, 69 but in the same model, TGF-␤ mRNA levels were reported to be elevated from days 3 to 18. 70 Regardless of its source, TGF-␤ has been shown to mediate intestinal healing in vitro (IEC-6) and in vivo (TGF-␤RII-DN transgenic mice).…”

Section: Discussionmentioning

confidence: 94%

Transforming Growth Factor-β Stimulates Intestinal Epithelial Focal Adhesion Kinase Synthesis via Smad- and p38-Dependent Mechanisms

Walsh

Ampasala

Hatfield

et al. 2008

The American Journal of Pathology

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Focal adhesion kinase (FAK) regulates cell migration, proliferation, and apoptosis. FAK protein is reduced at the edge of migrating gut epithelial sheets in vitro, but it has not been characterized in restitutive gut mucosa in vivo. Here we show that FAK and activated phospho-FAK (FAK 397 ) immunoreactivity was lower in epithelial cells immediately adjacent to human gastric and colonic ulcers in vivo, but dramatically increased in epithelia near the ulcers, possibly reflecting stimulation by growth factors absent in vitro. Transforming growth factor (TGF)-␤, but not fibroblast growth factor, platelet-derived growth factor, or vascular endothelial growth factor, increased FAK levels in Caco-2 and IEC-6 cells. Epithelial immunoreactivity to TGF-␤ and phospho-Smad3 was also higher near the ulcers, varying in parallel with FAK. The TGF-␤ receptor antagonist SB431542 completely blocked TGF-␤-induced Smad2/3 and p38 activation in IEC-6 cells. SB431542 , the p38 antagonist SB203580 , and siRNA-mediated reduction of Smad2 and p38␣ prevented TGF-␤ stimulation of both FAK transcription and translation (as measured via a FAK promoter-luciferase construct). Survival and function of epithelial cells depends critically on interactions between the extracellular matrix and cell surface integrins. These interactions are mediated through focal adhesions, multicomponent juxtamembrane structures that lie at the convergence of integrin adhesion, signaling, and the cytoskeleton.1 Focal adhesion kinase (FAK) is an important nonreceptor tyrosine kinase within the focal adhesion complex.2 Originally described as being rapidly tyrosine phosphorylated on integrin-mediated cell-matrix adhesion, FAK is now known to be activated during epithelial cell motility and phosphorylated at both serine and tyrosine residues by various factors.3-5 Once localized to sites of transmembrane integrin receptor clustering, tyrosine-phosphorylated FAK plays a central role in signal transduction triggered by diverse extracellular signals 6 and represents a convergent point for synergistic interaction between signal pathways activated by growth factors and integrins.7 FAK binds to different signaling proteins via Src homology 2 (SH2) and SH3 recognition sites, acting as a scaffold and transmitting signals crucial to cell survival, motility, proliferation, and differentiation.8 FAK also regulates the cycle of focal contact formation and disassembly required for efficient cell movement and thus, mucosal restitution. 9Levels of FAK protein expression and/or activation have been correlated to phenotypic changes that affect cell differentiation and function, notably adhesion and migration, in a number of tissues. 10 -13 Targeted FAK deletion in vascular endothelial cells leads to apoptosis and aberrant cell movement whereas FAK overexpression results in increased angiogenesis.14,15 Total and activated FAK levels are also directly related to the state of differentiation in human colon cancer. 16 Induction of differentiation in dedifferentiated, rounded, detached Co...

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Section: Discussionmentioning

confidence: 94%

Transforming Growth Factor-β Stimulates Intestinal Epithelial Focal Adhesion Kinase Synthesis via Smad- and p38-Dependent Mechanisms

Walsh

Ampasala

Hatfield

et al. 2008

The American Journal of Pathology

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“…TGFa has been detected throughout the mucosa of the gastrointestinal tract (48,49) as well as in intestinal epithelial and crypt derived cell lines (50), and may be involved in the response to injury (51)(52)(53). Although …”

Section: Resultsmentioning

confidence: 99%

Keratinocyte growth factor induces proliferation of hepatocytes and epithelial cells throughout the rat gastrointestinal tract.

Housley

Morris²,

Boyle³

et al. 1994

J. Clin. Invest.

262

200

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Keratinocyte growth factor (KGF), a member of the fibroblast growth factor (FGF) family, was identified as a specific keratinocyte mitogen after isolation from a lung fibroblast line. Recently, recombinant (r)KGF was found to influence proliferation and differentiation patterns of multiple epithelial cell lineages within skin, lung, and the reproductive tract. In the present study, we designed experiments to identify additional target tissues, and focused on the rat gastrointestinal (GI) system, since a putative receptor, K-sam, was originally identified in a gastric carcinoma. Expression of KGF receptor and KGF mRNA was detected within the entire GI tract, suggesting the gut both synthesized and responded to KGF. Therefore, rKGF was administered to adult rats and was found to induce markedly increased proliferation of epithelial cells from the foregut to the colon, and of hepatocytes, one day after systemic treatment. Daily treatment resulted in the marked selective induction of mucin-producing cell lineages throughout the GI tract in a dose-dependent fashion. Other cell lineages were either unaffected (e.g., Paneth cells), or relatively decreased (e.g., parietal cells, enterocytes) in rKGF-treated rats. The direct effect of rKGF was confirmed by demonstrating markedly increased carcinoembryonic antigen production in a human colon carcinoma cell line, LIM1899. Serum levels of albumin were specifically and significantly elevated after daily treatment. These results demonstrate rKIGF can induce epithelial cell activation throughout the GI tract and liver. Further, endogenous KGF may be a normal paracrine mediator of growth within the gut. (J. Clin. Iptvqst. 1994Iptvqst. . 94:1764Iptvqst. -1777

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“…Furthermore, cell-cell interaction between IECs and IELs is essential for the maintenance of an appropriate immunological homeostasis. IECs have been shown to produce a variety of cytokines and chemokines, including IL-6, IL-7, IL-8, IL-15, stem cell factor, TGF-␣, TGF-␤, monocyte chemoattractant protein 1, TNF-␣, and GM-CSF, which act as communication tools for the mucosal intranet (27)(28)(29)(30)(31)(32). Bacterial or viral invasion at the intestinal mucosa results in induction and/or up-regulation of cytokine and chemokine expression (31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

Autocrine IL-15 Mediates Intestinal Epithelial Cell Death Via the Activation of Neighboring Intraepithelial NK Cells

Kinoshita

Hiroi

Ohta

et al. 2002

The Journal of Immunology

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Intestinal intraepithelial lymphocytes (IELs), which reside between the basolateral faces of intestinal epithelial cells (IECs), provide a first-line defense against pathogens via their cytotoxic activity. Although IEC-derived IL-7 and IL-15 are key regulatory cytokines for the development and activation of IELs, we report here that IL-15 but not IL-7 mediates the reciprocal interaction between IELs and IECs, an important interaction for the regulation of appropriate mucosal immunohomeostasis. IL-15-treated IELs induced cell death in IECs via the cytotoxic activity in vitro. Among the different subsets of IL-15-treated IELs, CD4−CD8−TCR− IELs, which express NK marker (DX5 or NK1.1), showed the most potent syngenic IEC killing activity. These intraepithelial NK cells expressed Ly-49 molecules, NKG2 receptors, and perforin. These results suggest the possibility that the cell death program of IECs could be regulated by self-produced IL-15 through the activation of intraepithelial NK cells.

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Differential expression of transforming growth factors alpha and beta in rat intestinal epithelial cells.

Cited by 216 publications

References 27 publications

Transforming Growth Factor-β Stimulates Intestinal Epithelial Focal Adhesion Kinase Synthesis via Smad- and p38-Dependent Mechanisms

Transforming Growth Factor-β Stimulates Intestinal Epithelial Focal Adhesion Kinase Synthesis via Smad- and p38-Dependent Mechanisms

Keratinocyte growth factor induces proliferation of hepatocytes and epithelial cells throughout the rat gastrointestinal tract.

Autocrine IL-15 Mediates Intestinal Epithelial Cell Death Via the Activation of Neighboring Intraepithelial NK Cells

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