Early manifestations of NNK-induced lung cancer: role of lung immunity in tumor susceptibility.
A strong correlation exists between smoking and lung cancer; however, susceptibility to lung cancer among smokers is not uniform. Similarly, mice show differential susceptibility to the tobacco carcinogen nitrosamine 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which produces lung tumors in A/J but not in C3H mice. Host immunity may play a role in the susceptibility to cancer, and cigarette smoke/nicotine suppresses the immune system through activation of nicotinic acetylcholine receptors (nAChRs). Mammalian lungs express alpha7-nAChRs, and NNK is a high-affinity agonist for alpha7-nAChRs. To examine whether NNK differentially modulates lung immunity in susceptible and resistant mouse strains, A/J and C3H mice were treated with NNK and/or immunized with sheep red blood cells. Lung tissues and RNA of treated and untreated animals were analyzed by immunohistochemistry and RT-PCR for alpha7-nAChR and COX-2 expression. Spleen- and the lung-associated lymph node cells from control and immunized animals were assessed for immunologic responses, including anti-sheep red blood cell antibody plaque-forming cells, concanavalin A-induced T-cell proliferation, and the anti-CD3/CD28 antibody-induced rise in intracellular calcium. NNK strongly suppressed these responses in A/J but not in C3H mice. Similar NNK-induced immunologic changes were seen in another pair of carcinogen-sensitive (NGP) and relatively carcinogen-resistant (B10.A) mouse strains. Moreover, NNK stimulates a significantly higher expression of COX-2 and alpha7-nAChRs in A/J than in C3H lungs. These results suggest that the susceptibility to chemical carcinogenesis among various mouse strains might be influenced by their immunologic response to the carcinogen.
Razani-Boroujerdi
Seddigheh
S
Immunology Program, Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA.
Sopori
Mohan L
ML
D051997:ADP-ribosyl Cyclase 1 / Q000276:immunology; D000818:Animals; D017252:CD3 Complex / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004198:Disease Susceptibility; D004912:Erythrocytes / Q000276:immunology; D007114:Immunization; D008168:Lung / Q000276:immunology / Q000473:pathology*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000276:immunology*; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D009602:Nitrosamines; D011978:Receptors, Nicotinic / Q000378:metabolism; D013045:Species Specificity; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D064569:alpha7 Nicotinic Acetylcholine Receptor
D017252:CD3 Complex; C579166:Chrna7 protein, mouse; D009602:Nitrosamines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D051546:Cyclooxygenase 2; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium