Enhanced serum antigen-specific IgG1 and proinflammatory cytokine production in nicotinic acetylcholine receptor alpha7 subunit gene knockout mice.
Human and murine immune cells such as mononuclear leukocytes consisting of mainly T and B cells, bone marrow derived dendritic cells (DCs) and macrophages all express various nicotinic acetylcholine (ACh) receptor (nAChR) subunits. Activated T cells and DCs have the ability to synthesize ACh by choline acetyltransferase, suggesting the role of non-neuronal cholinergic system expressed in immune cells in the regulation of immune cell function. Stimulation of human leukemic T and B cell lines with nicotine causes a transient Ca(2+)-signaling that is antagonized by alpha-bungarotoxin, suggesting the involvement of alpha7 subunit. Furthermore, alpha7 nAChRs have been shown to negatively regulate synthesis and release of tumor necrosis factor (TNF)-alpha in macrophages. These findings suggest that immune cell function is regulated by its own non-neuronal cholinergic system, at least in part, via alpha7 nAChR-mediated pathways. In the present study, we tested the role of alpha7 nAChRs in the regulation of immune function by measuring total serum and antigen-specific IgG(1) and IgM, and production of TNF-alpha, gamma interferon (IFN-gamma) and interleukin (IL)-6 in activated spleen cells of nAChR alpha7 subunit gene knockout (alpha7 KO) and wild-type C57BL/6J mice immunized with ovalbumin (OVA). We found that serum levels of total and anti-OVA-specific IgG(1) were significantly elevated in alpha7 KO mice, though there were no significant differences in serum levels of total and anti-OVA-specific IgM between the two genotypes. Production of TNF-alpha, IFN-gamma and IL-6 in spleen cells was significantly facilitated in alpha7 KO mice. Expression of AChE mRNA was not different between the two genotypes. These results suggest that alpha7 nAChRs are involved in the regulation of cytokine production, through which modulates TNF-alpha, IFN-gamma and IL-6 productions, leading to modification of antibody production, but are not involved in expression of cholinergic components in immune cells.
Department of Pharmacology, Kyoritsu College of Pharmacy, Minato-ku, Tokyo 105-8512, Japan.
Yoshihito X
YX
Fujii
Hirofumi
H
Fujigaya
Yasuhiro
Y
Moriwaki
Hidemi
H
Misawa
Tadashi
T
Kasahara
Sergei A
SA
Grando
Koichiro
K
Kawashima
D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D007074:Immunoglobulin G / Q000097:blood*; D007075:Immunoglobulin M / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011978:Receptors, Nicotinic / Q000172:deficiency*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013154:Spleen / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D016207:Cytokines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D010047:Ovalbumin; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase