Effects of nicotine on the immune response. I. Chronic exposure to nicotine impairs antigen receptor-mediated signal transduction in lymphocytes.
Previous work has demonstrated that chronic exposure of rats to cigarette smoke causes inhibition of the antibody-forming cell (AFC) response and that the particulate phase of cigarette smoke, containing most of the nicotine in cigarette smoke, is essential for immunosuppression. Using intradermally implanted miniosmotic pumps, LEW rats were exposed to nicotine or its principal metabolite, cotinine, at the rate of about 14 micrograms/hr for 3-4 weeks. Serum cotinine levels in nicotine-treated (NT) animals of 219 +/- 40 ng/ml (on Day 10) were comparable to average human smokers. No significant differences between control (CON) and NT animals were observed in the distribution of lymphocyte subsets. However, nicotine, but not cotinine, treatment for 3 to 4 weeks inhibited both the T-dependent and T-independent AFC responses and proliferation to anti-CD3. Con A response was observed in 4-week but not in 3-week NT animals. Cell cycle analysis revealed that upon stimulation with Con A or anti-CD3, in spite of comparable surface expression of IL-2 receptors and class II MHC molecules, significantly fewer NT T cells entered the S and G2/M phases than CON T cells, indicating an arrest in the G0/G1 phase. Furthermore, B and T cells from NT animals were unable to elevate the intracellular calcium levels normally in response to ligation of antigen receptors, although Ca2+ responses of salivary gland cells to acetylcholine were normal. Thus, nicotine may significantly contribute to the immunosuppressive effects of chronic smoking by inducing a state of anergy in lymphocytes and may be related to their impaired response to antigen-induced signaling.
Immunotoxicology Section, Lovelace Institutes, Albuquerque, New Mexico 87108, USA.
Y
Y
Geng
S M
SM
Savage
L J
LJ
Johnson
J
J
Seagrave
M L
ML
Sopori
D000818:Animals; D000921:Antibody-Producing Cells / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002118:Calcium / Q000032:analysis; D002453:Cell Cycle / Q000187:drug effects; D003367:Cotinine / Q000633:toxicity; D019833:Genistein; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007529:Isoflavones / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D008297:Male; D009538:Nicotine / Q000633:toxicity*; D051381:Rats; D011917:Rats, Inbred Lew; D011946:Receptors, Antigen / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects*; D013047:Specific Pathogen-Free Organisms; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D000949:Histocompatibility Antigens Class II; D007529:Isoflavones; D011946:Receptors, Antigen; D015375:Receptors, Interleukin-2; D009538:Nicotine; D019833:Genistein; D003367:Cotinine; D002118:Calcium