Formyl peptide receptor-1 activation enhances intestinal epithelial cell restitution through phosphatidylinositol 3-kinase-dependent activation of Rac1 and Cdc42
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作者:
Babbin, Brian A.
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Emory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USAEmory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USA
Babbin, Brian A.
[1
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Jesaitis, Algirdas J.
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Montana State Univ, Dept Microbiol, Bozeman, MT 59715 USAEmory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USA
Jesaitis, Algirdas J.
[2
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Ivanov, Andrei I.
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Emory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USAEmory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USA
Ivanov, Andrei I.
[1
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Kelly, Daina
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Emory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USAEmory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USA
Kelly, Daina
[1
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Laukoetter, Mike
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Emory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USAEmory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USA
Laukoetter, Mike
[1
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Nava, Porfirio
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Emory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USAEmory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USA
Nava, Porfirio
[1
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Parkos, Charles A.
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Emory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USAEmory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USA
Parkos, Charles A.
[1
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Nusrat, Asma
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Emory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USAEmory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USA
Nusrat, Asma
[1
]
机构:
[1] Emory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USA
[2] Montana State Univ, Dept Microbiol, Bozeman, MT 59715 USA
Inflammatory disorders of the gastrointestinal tract result in the breakdown of the intestinal epithelial barrier in the form of erosion and ulceration. To reestablish the epithelial barrier, the epithelium must efficiently migrate to reseal wounds. Numerous signaling cascades are involved in the induction and regulation of this complex process. N-formyl peptide receptors comprise a group of G(i)-coupled receptors that regulate innate immune responses. Previously, we identified the expression of functional N-formyl peptide receptors in model SK-CO15 intestinal epithelial cells and observed a role for activation of these receptors in regulating cellular invasive behavior. In these studies, we performed formyl peptide receptor-1 (FPR) localization and evaluated its role in regulating intestinal epithelial cell wound closure. Immunolocalization studies using a recently developed specific monoclonal anti-FPR Ab demonstrated its localization along the lateral membrane of crypt epithelial cells in normal human colonic epithelium. In vitro studies using the classical FPR agonist fMLF showed that FPR activation significantly enhances model intestinal epithelial cell restitution and that FPR localized along actin filaments in lamellipodial and filopodial extrusions. The increase in cell migration was associated with activation of PI3K, Racl, and Cdc42. Pharmacologic inhibition of PI3K activity abrogated the fMLF-induced increase in wound closure and activation of both Rac1 and Cdc42. Inhibition of Rac1 and Cdc42 using pharmacologic inhibitors and dominant negative mutants also inhibited the fMLF-induced increase in cell migration. Taken together, theses results support a novel role for FPR stimulation in enhancing intestinal epithelial cell restitution through PI3K-dependent activation of Rac1 and Cdc42.
机构:
UCL Royal Free & Univ Coll Sch Med, Ludwig Inst Canc Res, London W1W 7BS, EnglandUCL Royal Free & Univ Coll Sch Med, Ludwig Inst Canc Res, London W1W 7BS, England
Cory, GOC
;
Ridley, AJ
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UCL Royal Free & Univ Coll Sch Med, Ludwig Inst Canc Res, London W1W 7BS, EnglandUCL Royal Free & Univ Coll Sch Med, Ludwig Inst Canc Res, London W1W 7BS, England
机构:
UCL Royal Free & Univ Coll Sch Med, Ludwig Inst Canc Res, London W1W 7BS, EnglandUCL Royal Free & Univ Coll Sch Med, Ludwig Inst Canc Res, London W1W 7BS, England
Cory, GOC
;
Ridley, AJ
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机构:
UCL Royal Free & Univ Coll Sch Med, Ludwig Inst Canc Res, London W1W 7BS, EnglandUCL Royal Free & Univ Coll Sch Med, Ludwig Inst Canc Res, London W1W 7BS, England