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

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

Research output: Contribution to journalArticle

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Abstract

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(4H)- benzopyran-4-one hydrochloride(LY294002)andwortmannin],calcium[1,2-bis(2- aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid- acetoxymethyl ester; BAPTAAM], phosphatidylinositol-phospholipase C (PLC) [1-[6-[[17β- methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122)], protein kinase C (PKC) [12-(2-cyanoethyl)-6,7,12, 13-tetrahydro-13-methyl-5-oxo- 5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole (Gö6976), rottlerin, and 3-1-[3-(amidinothio)propyl-1H-indol-3-yl]-3-(1-methyl-1H-indol-3-yl) maleimide (bisindolylmaleimide IX) (Ro 31-8220)], CaM (calmidazolium chloride), CaM kinase II [(8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl- 14-n- propoxy-2,3 ,9, 10-tetrahydro-8,11-epoxy, 1H,8H, 11H-2,7b,11a- 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.

Original languageEnglish
Pages (from-to)1454-1464
Number of pages11
JournalMolecular Pharmacology
Volume73
Issue number5
DOIs
Publication statusPublished - May 1 2008
Externally publishedYes

Fingerprint

calmidazolium
Histone Acetyltransferases
Adhesiveness
Vascular Cell Adhesion Molecule-1
Smooth Muscle Myocytes
Neutrophils
Phosphotransferases
Tumor Necrosis Factor-alpha
Histone Deacetylases
Phosphatidylinositol 3-Kinase
KN 62
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Phosphorylation
Type C Phospholipases
Protein Kinase C
trichostatin A
Trientine
Quinazolines
Calcium Chloride
Pyrroles

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Medicine
  • Pharmacology

Cite this

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

In: Molecular Pharmacology, Vol. 73, No. 5, 01.05.2008, p. 1454-1464.

Research output: Contribution to journalArticle

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abstract = "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(4H)- benzopyran-4-one hydrochloride(LY294002)andwortmannin],calcium[1,2-bis(2- aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid- acetoxymethyl ester; BAPTAAM], phosphatidylinositol-phospholipase C (PLC) [1-[6-[[17β- methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122)], protein kinase C (PKC) [12-(2-cyanoethyl)-6,7,12, 13-tetrahydro-13-methyl-5-oxo- 5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole (G{\"o}6976), rottlerin, and 3-1-[3-(amidinothio)propyl-1H-indol-3-yl]-3-(1-methyl-1H-indol-3-yl) maleimide (bisindolylmaleimide IX) (Ro 31-8220)], CaM (calmidazolium chloride), CaM kinase II [(8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl- 14-n- propoxy-2,3 ,9, 10-tetrahydro-8,11-epoxy, 1H,8H, 11H-2,7b,11a- 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.",
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T2 - 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

AU - Lee, Chiang Wen

AU - Lin, Chih Chung

AU - Luo, Shue Fen

AU - Lee, Hui Chun

AU - Lee, I. Ta

AU - Aird, William C.

AU - Hwang, Tsong Long

AU - Yang, Chuen Mao

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N2 - 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(4H)- benzopyran-4-one hydrochloride(LY294002)andwortmannin],calcium[1,2-bis(2- aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid- acetoxymethyl ester; BAPTAAM], phosphatidylinositol-phospholipase C (PLC) [1-[6-[[17β- methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122)], protein kinase C (PKC) [12-(2-cyanoethyl)-6,7,12, 13-tetrahydro-13-methyl-5-oxo- 5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole (Gö6976), rottlerin, and 3-1-[3-(amidinothio)propyl-1H-indol-3-yl]-3-(1-methyl-1H-indol-3-yl) maleimide (bisindolylmaleimide IX) (Ro 31-8220)], CaM (calmidazolium chloride), CaM kinase II [(8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl- 14-n- propoxy-2,3 ,9, 10-tetrahydro-8,11-epoxy, 1H,8H, 11H-2,7b,11a- 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.

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