Regulation of TNF-alpha- and IFN-gamma-induced CXCL10 expression: participation of the airway smooth muscle in the pulmonary inflammatory response in chronic obstructive pulmonary disease.
The chemokine CXCL10 is produced by many inflammatory cells found in the diseased lung and has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). The present study demonstrates elevated CXCL10 protein in the lungs of COPD patients, which appears histologically in airway smooth muscle (hASM). In primary cultured hASM cells taken from normal donors, CXCL10 protein expression was induced by IFN-gamma and TNF-alpha, cytokines reported as elevated in COPD, and a synergistic response was obtained when they were combined. TNF-alpha stimulation of hASM enhanced accumulation of CXCL10 mRNA, indicating regulation at the transcriptional level, while IFN-gamma stimulation resulted in a smaller accumulation of CXCL10 mRNA. When these cytokines were applied simultaneously, an additive effect was obtained. TNF-alpha-induced CXCL10 expression in hASM was dependent on NFkappaB activation, and a salicylanilide NFkappaB inhibitor blocked the CXCL10 expression. In contrast, IFN-gamma stimulation resulted in transient NFkappaB activation, and the inhibitor had little effect on CXCL10 expression. When these cytokines were added simultaneously, NFkappaB was activated earlier and lasted longer, and the effect was blocked by the inhibitor. These data demonstrate a potential active role for hASM in pulmonary inflammatory diseases such as COPD by producing CXCL10.
GlaxoSmithKline, Respiratory and Inflammation, Centre for Excellence in Drug Discovery, King of Prussia, Pennsylvania 19406, USA.
Elizabeth L
EL
Hardaker
Alicia M
AM
Bacon
Karey
K
Carlson
Amy K
AK
Roshak
James J
JJ
Foley
Dulcie B
DB
Schmidt
Peter T
PT
Buckley
Meghan
M
Comegys
Reynold A
RA
Panettieri
Henry M
HM
Sarau
Kristen E
KE
Belmonte
D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis*; D004357:Drug Synergism; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology*; D008168:Lung / Q000276:immunology*; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000473:pathology; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000378:metabolism; D012137:Respiratory System / Q000033:anatomy & histology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma