Inhibition of human interleukin-12 production by pentoxifylline.
Pharmacological control of interleukin-12 (IL-12) production may be a key therapeutic strategy for modulating immunological diseases dominated by type-1 cytokine responses. In this study, we investigated the effects of pentoxifylline on the production of IL-12 by human blood mononuclear cells and primary human monocytes stimulated with heat-killed Staphylococcus aureus Cowan strain I (SAC) or lipopolysaccharide (LPS). Pentoxifylline potently suppressed production of IL-12 in a concentration-dependent manner. In these same experiments, tumour necrosis factor-alpha (TNF-alpha) production was inhibited and IL-10 and prostaglandin E2 (PGE2) production was enhanced by treatment with pentoxifylline. Suppression of IL-12 production by pentoxifylline was found to be independent of several known endogenous inhibitors of IL-12, such as IL-10, transforming growth factor-beta (TGF-beta), IL-4 and PGE2. RNase protection assays revealed that pentoxifylline inhibited accumulation of both IL-12 p40 and p35 mRNA, suggesting a predominant mRNA locus for pentoxifylline-induced IL-12 inhibition. Low levels of pentoxifylline added to the suppression of IL-12 production by suboptimal inhibiting doses of dexamethasone, suggesting that this drug combination may have therapeutic utility. These results provide a firm rationale for the use of pentoxifylline in clinical trials of immunological disorders characterized by inappropriate type-1 immune responses.
Moller
D R
DR
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Wysocka
M
M
Greenlee
B M
BM
Ma
X
X
Wahl
L
L
Trinchieri
G
G
Karp
C L
CL
D018929:Cell Culture Techniques; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D016753:Interleukin-10 / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D010431:Pentoxifylline / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000276:immunology
D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12; D003907:Dexamethasone; D010431:Pentoxifylline; D007213:Indomethacin