Cytokine induction in mice by the immunomodulator imiquimod.
Imiquimod has been identified as a potent antiviral and antitumor agent in animal models. The biological activity associated with imiquimod has been attributed to its induction of interferon (IFN)-alpha. The present studies evaluated imiquimod administered orally for its ability to stimulate production of IFN and other cytokines in mice. The cytokine profile induced by imiquimod was compared with other known immunomodulators. Imiquimod was found to stimulate increased serum IFN in mice. Daily dosing of imiquimod for five consecutive days led to diminished production of IFN in mice as measured after the final dose. Elevated levels of serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 but not IL-1 alpha were found in serum from mice treated with imiquimod. Imiquimod produced significantly higher levels of IFN but lower levels of TNF and IL-6 and IL-1 alpha than lipopolysaccharide. Polyinosinic acid:polycytidylic acid induced significantly higher amounts of IFN but lower levels of TNF and IL-6 than imiquimod. Imiquimod stimulated significantly higher levels of IFN when compared with 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) and similar levels of IFN when compared with tilorone. Neither ABPP nor tilorone induced TNF or IL-6. Finally, imiquimod stimulated TNF, IFN, and IL-6 production in cultures of mouse spleen and bone marrow cells. These studies demonstrate that imiquimod induces not only IFN but other cytokines as well, all of which may contribute to its biological activity.
Reiter
M J
MJ
Dept of Pharmacology, 3M Pharmaceuticals, St. Paul, Minnesota 55144.
Testerman
T L
TL
Miller
R L
RL
Weeks
C E
CE
Tomai
M A
MA
D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism*; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D003596:Cytosine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D000077271:Imiquimod; D007369:Interferon Inducers / Q000494:pharmacology*; D007372:Interferons / Q000096:biosynthesis* / Q000097:blood; D007375:Interleukin-1 / Q000096:biosynthesis / Q000097:blood; D015850:Interleukin-6 / Q000096:biosynthesis; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011070:Poly I-C / Q000494:pharmacology; D012486:Salmonella typhimurium; D013154:Spleen / Q000166:cytology; D013994:Tilorone / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000634:Aminoquinolines; D016207:Cytokines; D007369:Interferon Inducers; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D003596:Cytosine; D007372:Interferons; C033560:bropirimine; D013994:Tilorone; D011070:Poly I-C; D000077271:Imiquimod