AN INHIBITOR OF POLYAMINE BIOSYNTHESIS IMPAIRS HUMAN POLYMORPHONUCLEAR LEUKOCYTE PRIMING BY TUMOR-NECROSIS-FACTOR-ALPHA

TNF primes polymorphonuclear leukocytes (PMNs) for enhanced oxidative and secretory activity and directly induces adhesion and IL-1 beta exp ression. Previous reports suggest that polyamine biosynthesis by ornit hine decarboxylase (ODC) has an essential role in macrophage activatio n by TNF. In the current study, TNF induced rapid increases in the put rescine and spermine content of PMNs. Difluoromethylornithine (DFMO), a selective inhibitor of ODC, inhibited these increases and blunted th e enhancement of superoxide generation and secondary granule release a ssociated with priming by TNF. DFMO did not affect the expression of T NF receptors or block receptor-independent activation of the respirato ry burst by phorbol esters. Moreover, DFMO did not antagonize inductio n of adhesion or IL-1 beta mRNA expression by TNF. Thus, polyamine bio synthesis plays an important role in priming by TNF, but is not involv ed in all PMN responses to this cytokine. This suggests that ODC is a potential target for selective chemotherapeutic modulation of the infl ammatory response.