Differential effects of pentoxifylline, a non-specific phosphodiesterase inhibitor, on the production of IL-10, IL-12 p40 and p35 subunits by murine peritoneal macrophages.
Pentoxifylline (PTX), a methylxanthine derivative, has been reported to be an effective drug in inhibiting TNF-alpha responses during septic shock. The inhibition of TNF-alpha production seems to be correlated with increased intracellular cAMP levels. PTX also affects the production of other cytokines such as IL-1, IL-6, IL-10, IL-12, and IFN-gamma. However, inhibition, as well as enhancement of cytokine production, has been observed in vitro, depending on the PTX concentration and cell type used.IL-12 is a heterodimeric cytokine that plays an important role in the development of Th1-mediated inflammatory responses. IL-12 along with TNF-alpha and other proinflammatory cytokines has shown to be responsible for the pathological reaction, which may lead to septic shock. For biological activity, the expression of both subunits of IL-12, p35 and p40, is required. Moreover, the p40 chain of IL-12 specifically inhibits the effects of the IL-12 heterodimer. In this study, we investigated the effects of PTX on the production of both proinflammatory (TNF-alpha, IL-6, IL-12) and anti-inflammatory (IL-10) cytokines by murine macrophages (M&phi;). We have found that PTX, at concentrations below 100 microg/ml, selectively inhibited the production of TNF-alpha. Forskolin, a cAMP-elevating agent, similarly affected the production of the cytokines tested. However, at higher concentrations, PTX inhibited the production of TNF-alpha, IL-10, and IL-12 p35, but surprisingly, PTX enhanced the production of IL-12 p40. Concentrations of IL-10 were negatively correlated with the concentrations of IL-12 p40 subunit. These results further confirm the relevance of the use of PTX in clinical trials of immunological disorders characterised by inappropriate Th1 type immune responses.
Marcinkiewicz
J
J
Department of Immunology, Jagiellonian University Medical College, 18 Czysta Street, 31-121, Cracow, Poland. mmmarcin@cyf-edu.kr-pl
Grabowska
A
A
Lauterbach
R
R
Bobek
M
M
D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004338:Drug Combinations; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010431:Pentoxifylline / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D018417:Th1 Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
D016207:Cytokines; D004338:Drug Combinations; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D016753:Interleukin-10; D018664:Interleukin-12; D005576:Colforsin; D007371:Interferon-gamma; D000242:Cyclic AMP; D010431:Pentoxifylline