Production of proinflammatory cytokines and cytokines involved in the TH1/TH2 balance is modulated by pentoxifylline.
The modulation of cytokine release induced by pentoxifylline (PTX) has recently been demonstrated not to be restricted solely to tumor necrosis factor (TNF)-alpha. This prompted us to study the influence of PTX on a larger spectrum of cytokines with proinflammatory actions [TNF-alpha, interleukin-6, (IL)-6, IL-1 beta, IL-8] or with implied actions in the TH1 (IL-2, IFN-gamma)/TH2 (IL-10) balance. The IL-1RA was also explored. This work was performed using a whole-blood model in which cytokine production is measured after stimulation by lipopolysaccharide (LPS) (25 micrograms/ml) and phytohemagglutinin (PHA) (5 micrograms/ml) in 1:10 diluted whole blood. The stimulation test was performed in blood from healthy controls and from septic patients (without septic shock) in the presence or absence of PTX at 10(-6), 10(-5), 10(-4), or 10(-3) M. In controls and septic patients, at a 10(-4) M PTX concentration the production of IL-2 is strongly diminished (26-32% of the basal level), followed by diminution of IFN-gamma (30-40%). As expected, of the proinflammatory cytokines TNF was the most strongly suppressed (50% of baseline) followed by IL-1 (about 80% of basal production). Finally, IL-10 was also influenced by PTX (65% of baseline). At 10(-4) M, IL-1RA and IL-6 were unaffected by PTX. Taken altogether, our data demonstrate that PTX possesses a much broader spectrum of activity on cytokine production than was initially described, and it appears to be a potential and promising immunotherapeutic agent.
Bienvenu
J
J
Laboratoire d'Immunologie, Centre Hospitalier Lyon-Sud, Pierre Benite, France.
Doche
C
C
Gutowski
M C
MC
Lenoble
M
M
Lepape
A
A
Perdrix
J P
JP
D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis* / Q000502:physiology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D010431:Pentoxifylline / Q000494:pharmacology*; D010835:Phytohemagglutinins / Q000494:pharmacology; D018805:Sepsis / Q000378:metabolism; D018417:Th1 Cells / Q000502:physiology*; D018418:Th2 Cells / Q000502:physiology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D010835:Phytohemagglutinins; D010431:Pentoxifylline