IL-18 is induced and IL-18 receptor alpha plays a critical role in the pathogenesis of cigarette smoke-induced pulmonary emphysema and inflammation.
Th1 inflammation and remodeling characterized by local tissue destruction coexist in pulmonary emphysema and other diseases. To test the hypothesis that IL-18 plays an important role in these responses, we characterized the regulation of IL-18 in lungs from cigarette smoke (CS) and room air-exposed mice and characterized the effects of CS in wild-type mice and mice with null mutations of IL-18Ralpha (IL-18Ralpha(-/-)). CS was a potent stimulator and activator of IL-18 and caspases 1 and 11. In addition, although CS caused inflammation and emphysema in wild-type mice, both of these responses were significantly decreased in IL-18Ralpha(-/-) animals. CS also induced epithelial apoptosis, activated effector caspases and stimulated proteases and chemokines via IL-18Ralpha-dependent pathways. Importantly, the levels of IL-18 and its targets, cathepsins S and B, were increased in pulmonary macrophages from smokers and patients with chronic obstructive lung disease. Elevated levels of circulating IL-18 were also seen in patients with chronic obstructive lung disease. These studies demonstrate that IL-18 and the IL-18 pathway are activated in CS-exposed mice and man. They also demonstrate, in a murine modeling system, that IL-18R signaling plays a critical role in the pathogenesis of CS-induced inflammation and emphysema.
Kang
Min-Jong
MJ
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Homer
Robert J
RJ
Gallo
Amy
A
Lee
Chun Geun
CG
Crothers
Kristina A
KA
Cho
Soo Jung
SJ
Rochester
Carolyn
C
Cain
Hilary
H
Chupp
Geoffrey
G
Yoon
Ho Joo
HJ
Elias
Jack A
JA
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D004847:Epithelial Cells; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D020382:Interleukin-18 / Q000097:blood / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010447:Peptide Hydrolases / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000209:etiology* / Q000473:pathology; D053724:Receptors, Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana
D018925:Chemokines; D020382:Interleukin-18; D053724:Receptors, Interleukin-18; D012906:Smoke; D010447:Peptide Hydrolases; D020169:Caspases