The Journal of allergy and clinical immunology · 2012
Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma.
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Chang Po-Jui, Bhavsar Pankaj K, Michaeloudes Charalambos, Khorasani Nadia, Chung Kian Fan
Аннотация
BACKGROUND: Patients with severe asthma are less responsive to the beneficial effects of corticosteroid therapy.
OBJECTIVE: We investigated whether corticosteroid insensitivity was present in airway smooth muscle cells (ASMCs) of patients with severe asthma.
METHODS: ASMCs cultured from bronchial biopsy specimens of nonasthmatic control subjects (n = 12) and patients with nonsevere (n = 10) or severe (n = 10) asthma were compared for the effect of dexamethasone on suppression of TNF-α- and IFN-γ-induced CCL11 (eotaxin), CXCL8 (IL-8), and CX3CL1 (fractalkine) expression. The mechanisms of corticosteroid insensitivity are also determined.
RESULTS: CCL11 release was higher in ASMCs of patients with nonsevere but not severe asthma and nonasthmatic control subjects; CXCL8 and CX3CL1 release were similar in all groups. In patients with severe asthma, dexamethasone caused less suppression of CCL11 and CXCL8 release induced by TNF-α. Dexamethasone potentiated TNF-α- and IFN-γ-induced CX3CL1 release equally in all 3 groups. TNF-α-induced phosphorylated p38 mitogen-activated protein kinase levels were increased in ASMCs from patients with severe asthma compared with those from patients with nonsevere asthma and nonasthmatic subjects, whereas TNF-α-induced phosphorylated c-Jun N-terminal kinase and phosphorylated extracellular signal-related kinase levels were increased in all asthmatic groups. A p38 inhibitor increased the inhibitory effect of dexamethasone.
CONCLUSIONS: ASMCs of patients with severe asthma are corticosteroid insensitive; this might be secondary to heightened p38 mitogen-activated protein kinase levels.
OBJECTIVE: We investigated whether corticosteroid insensitivity was present in airway smooth muscle cells (ASMCs) of patients with severe asthma.
METHODS: ASMCs cultured from bronchial biopsy specimens of nonasthmatic control subjects (n = 12) and patients with nonsevere (n = 10) or severe (n = 10) asthma were compared for the effect of dexamethasone on suppression of TNF-α- and IFN-γ-induced CCL11 (eotaxin), CXCL8 (IL-8), and CX3CL1 (fractalkine) expression. The mechanisms of corticosteroid insensitivity are also determined.
RESULTS: CCL11 release was higher in ASMCs of patients with nonsevere but not severe asthma and nonasthmatic control subjects; CXCL8 and CX3CL1 release were similar in all groups. In patients with severe asthma, dexamethasone caused less suppression of CCL11 and CXCL8 release induced by TNF-α. Dexamethasone potentiated TNF-α- and IFN-γ-induced CX3CL1 release equally in all 3 groups. TNF-α-induced phosphorylated p38 mitogen-activated protein kinase levels were increased in ASMCs from patients with severe asthma compared with those from patients with nonsevere asthma and nonasthmatic subjects, whereas TNF-α-induced phosphorylated c-Jun N-terminal kinase and phosphorylated extracellular signal-related kinase levels were increased in all asthmatic groups. A p38 inhibitor increased the inhibitory effect of dexamethasone.
CONCLUSIONS: ASMCs of patients with severe asthma are corticosteroid insensitive; this might be secondary to heightened p38 mitogen-activated protein kinase levels.