CCR3 induced-p42/44 MAPK activation protects against staurosporine induced-DNA fragmentation but not apoptosis in airway smooth muscle cells

Summary Background Chemokine receptors (CCRs) are expressed on airway smooth muscle (ASM) cells. As their ligands are present in the airways in asthma, we hypothesized that ASM CCR activation could promote the increase in ASM mass seen in patients with chronic asthma. Objective To determine which CC...

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Vydané v:	Clinical and experimental allergy Ročník 42; číslo 7; s. 1040 - 1050
Hlavní autori:	Markwick, L. J., Clements, D., Roberts, M. E., Ceresa, C. C., Knox, A. J., Johnson, S. R.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Oxford Blackwell Publishing Ltd 01.07.2012 Blackwell Wiley Subscription Services, Inc
Predmet:	airway remodelling AKT protein Apoptosis Apoptosis - drug effects Asthma Asthma - metabolism Asthma - pathology Biological and medical sciences Biopsy Bronchi - metabolism Bronchi - pathology Caspase 3 - metabolism Caspase-3 CD95 antigen Cell culture Cells, Cultured chemokine Chemokine receptors Chronic obstructive pulmonary disease, asthma CX3CR1 protein DNA fragmentation DNA Fragmentation - drug effects Enzyme Activation - drug effects Enzyme Inhibitors - adverse effects Enzyme Inhibitors - pharmacology Epithelium Fas antigen Female Flow cytometry Fundamental and applied biological sciences. Psychology Fundamental immunology Humans Immunohistochemistry Male MAP kinase Medical sciences Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - metabolism Myocytes, Smooth Muscle - metabolism Myocytes, Smooth Muscle - pathology Pneumology Polymerase chain reaction Receptors, CCR3 - biosynthesis Respiratory tract Smooth muscle Staurosporine Staurosporine - adverse effects Staurosporine - pharmacology Thymidine Vascular endothelial growth factor Western blotting Lung disease Enzyme Respiratory disease Transferases airway remodelling Mitogen-activated protein kinase Smooth muscle Activation Chemokine receptor CCR3 chemokine receptor Remodeling Respiratory system Asthma Fragmentation Myocyte Chemokine Respiratory tract Immunology Cell death DNA Bronchus disease Obstructive pulmonary disease Protection Apoptosis
ISSN:	0954-7894, 1365-2222, 1365-2222
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Shrnutí:	Summary Background Chemokine receptors (CCRs) are expressed on airway smooth muscle (ASM) cells. As their ligands are present in the airways in asthma, we hypothesized that ASM CCR activation could promote the increase in ASM mass seen in patients with chronic asthma. Objective To determine which CCRs are expressed by ASM cells and their potential functional relevance to the chronic airway changes seen in asthma. Methods CCR expression in primary ASM cell cultures and airway biopsies from patients with and without asthma was examined by RT‐PCR, fluorescence‐activated cell sorting and immunohistochemistry. ASM p42/44 MAPK activity, proliferation, migration and apoptosis were examined by western blotting, thymidine incorporation, transwell assay and TUNEL assay respectively. Results CCR3 was the most frequently expressed CCR protein and was present on 79 ± 14% of cells. CX3CR1 and CXCR6 were present on 6% and 11% of cells respectively. CCR3 ligands CCL11 and CCL24 caused rapid activation of p42/44 MAPK but not Akt. CCR3 activation did not affect ASM proliferation, migration or VEGF secretion. DNA fragmentation detected by TUNEL staining could be induced by staurosporine and Fas activation although only Fas activation resulted in caspase 3 cleavage. CCL11 and CCL24 protected ASM cells against DNA fragmentation dependent upon p42/44 MAPK activity only via caspase 3 independent pathways. CCR3 was expressed in the smooth muscle and epithelium in the airways of patients with and without asthma. Smooth muscle cell DNA fragmentation in the airways of patients with stable asthma and controls was very uncommon. Conclusions and Clinical Relevance CCR3 is strongly expressed by ASM cells in vitro and in vivo. Protection against cell death by CCR3 activation is dependent on p42/44 MAPK but does not affect caspase 3 mediated apoptosis.
Bibliografia:	ArticleID:CEA4019 istex:A1E1033C4C6EF70EA6555ED89487EF3ABDDF1A74 ark:/67375/WNG-0BSZ86BR-S Fig. S1. Activation of p42/44 MAPK but not Akt by chemokine ligands.Fig. S2. Chemokines do not affect ASM migration.Fig. S3. Chemokines do not affect ASM proliferation.Fig. S4. The effect of protease inhibitors on the activation of p44/42 MAPK by CCL11, CX3CL1, CCL24, CXCL16, and CCL28. University of Nottingham and Asthma - No. 05/007 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23
ISSN:	0954-7894 1365-2222 1365-2222
DOI:	10.1111/j.1365-2222.2012.04019.x