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Endothelial ICAM-1 protein induction is regulated by cytosolic phospholipase A2α via both NF-κB and CREB transcription factors.
Hadad, Nurit; Tuval, Liron; Elgazar-Carmom, Vered; Levy, Ron; Levy, Rachel.
Affiliation
  • Hadad N; Infectious Disease and Immunology Laboratory, Clinical Biochemistry Department, Faculty of Health Sciences, Soroka Medical University Center and Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
J Immunol ; 186(3): 1816-27, 2011 Feb 01.
Article in En | MEDLINE | ID: mdl-21199900
The regulated expression of ICAM-1 plays an important role in inflammatory processes and immune responses. The present study aimed to determine the in vivo involvement of cytosolic phospholipase A(2)α (cPLA(2)α) in ICAM-1 overexpression during inflammation and to elucidate the cPLA(2)α-specific role in signal events leading to ICAM-1 upregulation in endothelial cells. cPLA(2)α and ICAM-1 upregulation were detected in inflamed paws of mice with collagen-induced arthritis and in periepididymal adipose tissue of mice fed a high-fat diet. Intravenous injection of 2 mg/kg oligonucleotide antisense against cPLA(2)α (AS) that reduced cPLA(2)α upregulation also decreased ICAM-1 overexpression, suggesting a key role of cPLA(2)α in ICAM-1 upregulation during inflammation. Preincubation of endothelial ECV-304 cells that express ICAM-1 and of HUVEC that express ICAM-1 and VCAM-1 with 1 µM AS prevented cPLA(2)α and the adhesion molecule upregulation induced by TNF-α and inhibited their adherence to phagocyte like-PLB cells. Whereas AS did not inhibit NADPH oxidase 4-NADPH oxidase activity, inhibition of oxidase activity attenuated cPLA(2)α activation, suggesting that NADPH oxidase acts upstream to cPLA(2)α. Attenuating cPLA(2)α activation by AS or diphenylene iodonium prevented the induction of cyclooxygenase-2 and the production of PGE(2) that were essential for ICAM-1 upregulation. Inhibition of cPLA(2)α activity by AS inhibited the phosphorylation of both p65 NF-κB on Ser(536) and protein kinase A-dependent CREB. To our knowledge, our results are the first to show that CREB activation is involved in ICAM-1 upregulation and suggest that cPLA(2)α activated by NADPH oxidase is required for sequential phosphorylation of NF-κB by an undefined kinase and CREB activation by PGE(2)-mediated protein kinase A.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Endothelium, Vascular / NF-kappa B / Cyclic AMP Response Element-Binding Protein / Intercellular Adhesion Molecule-1 / Group IV Phospholipases A2 Limits: Animals / Humans / Male Language: En Journal: J Immunol Year: 2011 Document type: Article Affiliation country: Israel Country of publication: Estados Unidos

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Endothelium, Vascular / NF-kappa B / Cyclic AMP Response Element-Binding Protein / Intercellular Adhesion Molecule-1 / Group IV Phospholipases A2 Limits: Animals / Humans / Male Language: En Journal: J Immunol Year: 2011 Document type: Article Affiliation country: Israel Country of publication: Estados Unidos