METHYLXANTHINES WITH ADENOSINE ALTER TNF-ALPHA-PRIMED PMN ACTIVATION

Methylxanthines are best known as phosphodiesterase inhibitors that ca use a rise in intracellular cAMP. One would expect the two methylxanth ines, caffeine and pentoxifylline, to have similar actions on neutroph ils (PMN). However, caffeine stimulated and pentoxifylline inhibited P MN oxidative activity. Micromolar concentrations of pentoxifylline dec reased native and recombinant tumor necrosis factor-alpha (TNF alpha)- primed formyl met-leu-phe (fMLP)-stimulated PMN chemiluminescence, sup eroxide production and myeloperoxidase (MPO) release. In contrast, equ al concentrations of caffeine increased chemiluminescence and MPO rele ase with no effect on superoxide production. These activities of the m ethylxanthines were only observed in the presence of physiological con centrations of adenosine, and were abolished by the treatment of the P MN with adenosine deaminase. The activities of adenosine, pentoxifylli ne and caffeine on PMN activity could not be readily explained by chan ges in PMN [cAMP]. Thus for TNF alpha-primed PMN: pentoxifylline decre ases PMN activity by enhancing the effect of adenosine on degranulatio n and superoxide production; whereas caffeine increases PMN activity b y counteracting the effect of adenosine on degranulation.