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Tumor Necrosis Factor-α Enhances Neutrophil Adhesiveness: Induction of Vascular Cell Adhesion Molecule-1 via Activation of Akt and CaM Kinase II and Modifications of Histone Acetyltransferase and Histone Deacetylase 4 in Human Tracheal Smooth Muscle Cells

2008; American Society for Pharmacology and Experimental Therapeutics; Volume: 73; Issue: 5 Linguagem: Inglês

10.1124/mol.107.038091

1521-0111

Chiang‐Wen Lee, Chih‐Chung Lin, Shue‐Fen Luo, Hui-Chun Lee, I.-Ta Lee, William C. Aird, Tsong‐Long Hwang, Chuen‐Mao Yang,

Protease and Inhibitor Mechanisms

Up-regulation of vascular cell adhesion molecule-1 (VCAM-1) involves adhesions between both circulating and resident leukocytes and the human tracheal smooth muscle cells (HTSMCs) during airway inflammatory reaction. We have demonstrated previously that tumor necrosis factor (TNF)-α-induced VCAM-1 expression is regulated by mitogen-activated protein kinases, nuclear factor-κB, and p300 activation in HTSMCs. In addition to this pathway, phosphorylation of Akt and CaM kinase II has been implicated in histone acetyltransferase and histone deacetylase 4 (HDAC4) activation. Here, we investigated whether these different mechanisms participated in TNF-α-induced VCAM-1 expression and enhanced neutrophil adhesion. TNF-α significantly increased HTSMC-neutrophil adhesions, and this effect was associated with increased expression of VCAM-1 on the HTSMCs and was blocked by the selective inhibitors of Src [4-amino-5-(4-methylphenyl)-7-( t -butyl)pyrazolo[3,4- d ]-pyrimidine (PP1)], epidermal growth factor receptor [EGFR; 4-(3′-chloroanilino)-6,7-dimethoxy-quinazoline, (AG1478)], phosphatidylinositol 3-kinase (PI3K) [2-(4-morpholinyl)-8-phenyl-1(4 H )-benzopyran-4-one hydrochloride(LY294002) and wortmannin],calcium[1,2-bis(2-aminophenoxy) ethane- N , N , N ′, N ′-tetraacetic acid-acetoxymethyl ester; BAPTA-AM], phosphatidylinositol-phospholipase C (PLC) [1-[6-[[17β-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1 H -pyrrole-2,5-dione (U73122)], protein kinase C (PKC) [12-(2-cyanoethyl)-6,7,12, 13-tetrahydro-13-methyl-5-oxo-5 H -indolo(2,3- a )pyrrolo(3,4- c )-carbazole (Gö6976), rottlerin, and 3-1-[3-(amidinothio)propyl-1 H -indol-3-yl]-3-(1-methyl-1 H -indol-3-yl) maleimide (bisindolylmaleimide IX) (Ro 31-8220)], CaM (calmidazolium chloride), CaM kinase II [(8 R * ,9 S * ,11 S * )-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-14- n -propoxy-2,3,9, 10-tetrahydro-8,11-epoxy, 1 H ,8 H , 11 H -2,7 b ,11 a -triazadibenzo[ a,g ]cycloocta[ cde ]trinden-1-one (KT5926) and 1-[ N , O -bis(5-isoquinolinesulfonyl)- N -methyl-l-tyrosyl]-4-phenylpiperazine (KN62)], p300 (curcumin), and HDAC (trichostatin A) or transfection with short interfering RNAs for Src, Akt, PKCα, PKCμ, and HDAC4. At gene regulation level, reverse-transcriptase polymerase chain reaction and promoter assays revealed that expression of VCAM-1 was also attenuated by these signaling molecule inhibitors. Moreover, TNF-α induced Akt and CaM kinase II phosphorylation via cascades through Src/EGFR/PI3K and PLC/calcium/CaM, respectively. Finally, activation of Akt and CaM kinase II may eventually lead to the acetylation of histone residues and phosphorylation of histone deacetylase. These findings revealed that TNF-α induced VCAM-1 expression via multiple signaling pathways. Blockade of these pathways may be selectively targeted to reduce neutrophil adhesion via VCAM-1 suppression and attenuation of the inflammatory responses in airway diseases.