Inhibition of the inflammatory action of interleukin-1 and tumor necrosis factor (alpha) on neutrophil function by pentoxifylline

Abstract

Inflammatory cytokines, including interleukin-l and tumor necrosis factor, are produced by monocytes and macrophages in response to microorganisms and microbial products such as endotoxins. The cytokines stimulate neutrophil adherence, degranulation, and superoxide production but inhibit neutrophil migration. We studied the modulation of cytokine-induced neutrophil activation by pentoxifylline and its principle metabolites. Lipopolysaccharide-stimulated mononuclear-leukocyte-conditioned medium containing inflammatory cytokines, purified human interleukin-l, or recombinant human tumor necrosis factor increased neutrophil adherence to nylon fiber, primed neutrophils for increased superoxide production in response to N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP), increased neutrophil lysozyme release stimulated by FMLP, and decreased directed migration of neutrophils to FMLP. Pentoxifylline and its principle metabolites at or near therapeutically achievable levels were able to counteract these effects. Pentoxifylline inhibited the increase in free intracellular calcium in polymorphonuclear leukocytes stimulated by FMLP and increased binding of FMLP to neutrophils at 37°C but not at 4°C. By blocking the inflammatory action of interleukin-l and tumor necrosis factor on neutrophils, pentoxifylline may diminish the tissue damage caused by neutrophils in such conditions as septic shock, adult respiratory distress syndrome, cardiopulmonary bypass lung damage, and myocardial reperfusion injury.

Retracted: Evaluation of the effect of pentoxifylline on white blood cell count in serum and peritoneal fluid in female rats with endometriosis

“…Pentoxifylline reduces both the production and action of cytokines such as TNF-a through the elevation of intracellular cyclic cAMP levels, and subsequent down-regulation of cytokine production and action. 4,5,12 Pentoxifylline is a member of the methylgezantine family which inhibits phosphodiesterase in platelets and leads to the elevation of cAMP levels and the decrease in the aggregation of platelets in R e t r a c t e d circulation. Pentoxifylline is therefore useful in the treatment of cerebrovascular diseases.…”

“…4,5,13 Pentoxifylline can inhibit phosphodiesterase in monocytes and macrophages, and suppress cytokine production, specially TNF-a, in macrophages. 4,5,12,13 Pentoxifylline has been useful in the treatment of rheumatoid artheritis 14 and inflammatory bowel disease. 15 It seems that the anti-TNF-a effect of this drug can be useful in the treatment of endometriosis.…”

Splenocyte apoptosis in Plasmodium berghei ANKA infection: possible role of TNF‐α and TGF‐β

“…The use of this immunomodulatory drug in plasmodium-infected mice usually showed better results than its use in humans, probably due to a better controlled experimental design and the precocious onset of treatment in the experimental models. Pentoxifylline also increases deformability of red blood cells, thereby counteracting the decreased deformability of infected erythrocytes (28,67). Pentoxifylline was found to increase intracellular cAMP levels (68), which further enhances anti-inflammatory effects by reducing the release of cytokines, histamine and leukotrienes (69)(70)(71).…”

Pentoxifylline decreases neutrophil respiratory bursts in patients with stable angina

“…Trials undertaken recently have demonstrated that pentoxifylline is a free radical scavenger [21], and lowers superoxide production in neutrophils stimulated by fh4LP [ 19,22,231 but not in those stimulated by phorbol esters (PMA). This suggests that pentoxifylline may act at the receptor level.…”