Cellular requirements for cytokine production in response to the immunomodulators imiquimod and S-27609.
Imiquimod (R-837) and its analog, S-27609, belong to a class of imidazoquinolinamines that have potent antitumor and antiviral effects in animals. Much of their biologic activity is a result of the induction of cytokines, including interferon-alpha (IFN-alpha), tumor necrosis factor alpha (TNF), and others. In this study, the cells responsible for S-27609- and imiquimod-induced cytokine production were characterized. E rosette+ T cells were not the major cell population responsible for IFN-alpha and TNF in response to S-27609 or imiquimod. In contrast, E rosette- cells and unseparated PBMC produced similar concentrations of IFN-alpha and TNF in response to S-27609 and imiquimod. Elimination of monocytes by treatment with the lysosomotropic agent L-leucine methyl ester (LME) or depletion using antibody to CD14 and immunomagnetic beads abrogated IFN-alpha and TNF production induced by S-27609, imiquimod, or LPS but not poly(I)/(C). LME treatment also abolished interleukin (IL)-1 alpha, IL-beta, IL-6, and IL-8 production stimulated by S-27609 and imiquimod. Removal of HLA-DR+ or CD36+ monocytes also caused a significant reduction in S-27609- and imiquimod-induced IFN-alpha and TNF. Elimination of B cells, NK cells, and dendritic cells did not significantly reduce cytokine induction in response to S-27609. Thus, the cell population responsible for the majority of cytokine release in human PBMC in response to S-27609 and imiquimod is a E rosette-, CD14+, CD36+, HLA-DR+ monocyte.
Gibson
S J
SJ
Department of Pharmacology, 3M Pharmaceuticals, St. Paul, MN 55144, USA.
Imbertson
L M
LM
Wagner
T L
TL
Testerman
T L
TL
Reiter
M J
MJ
Miller
R L
RL
Tomai
M A
MA
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000634:Aminoquinolines / Q000494:pharmacology*; D018955:CD36 Antigens / Q000097:blood; D016207:Cytokines / Q000096:biosynthesis*; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D000077271:Imiquimod; D007369:Interferon Inducers / Q000494:pharmacology*; D018950:Lipopolysaccharide Receptors / Q000097:blood; D009000:Monocytes / Q000276:immunology
C095471:4-amino-alpha,alpha,2-trimethyl-1H-imidazo(4,5-c)quinoline-1-ethanol; D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D018955:CD36 Antigens; D016207:Cytokines; D006684:HLA-DR Antigens; D007369:Interferon Inducers; D018950:Lipopolysaccharide Receptors; D000077271:Imiquimod