Pentoxifylline induces the shedding of L-selectin on polymorphonuclear cells by stimulation via adenosine receptor as well as by the inhibition of phosphodiesterase

Abstract

We investigated the effects of pentoxifylline (PTX) on the expression of L-selectin on polymorphonuclear leukocytes (PMN). PTX induced the down-regulation of L-selectin expression in dose- and time-dependent manner. The measurement of soluble L-selectin in the culture medium by ELISA indicated that the down-regulation of L-selectin expression by PTX was due to the shedding of L-selectin from PMN. The mechanism by which PTX induced the shedding of L-selectin was investigated. The concentration of intracellular cyclic AMP (cAMP) was increased after treatment of PMN with PTX. However, an elevation of cAMP induced by dibutyryl cAMP (dbcAMP) as well as other methylxanthine derivatives (caffeine, aminophylline, and theophylline) did not induce the shedding of L-selectin. Although stimulation of the adenosine receptor with 5′-N-ethylcarboxamidoadenosine (NECA) or 5′-(N-cyclopropyl)-carboxamido-adenosine (CPCA) adenosine receptor agonists did not induce the shedding of L-selectin, shedding of L-selectin was demonstrated when PMN was incubated simultaneously with rolipram, a phosphodiesterase (PDE) inhibitor, and CPCA. Moreover, shedding of L-selectin induced by PTX was attenuated by aminophylline, an adenosine receptor antagonist. These results indicated that PTX induces the shedding of L-selectin on PMN by stimulation via the adenosine receptor as well as inhibition of PDE.