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 expression. Previous reports suggest that polyamine biosynthesis by ornithine decarboxylase (ODC) has an essential role in macrophage activation by TNF. In the current study, TNF induced rapid increases in the putrescine and spermine content of PMNs. Difluoromethylornithine (DFMO), a selective inhibitor of ODC, inhibited these increases and blunted the enhancement of superoxide generation and secondary granule release associated with priming by TNF. DFMO did not affect the expression of TNF receptors or block receptor-independent activation of the respiratory burst by phorbol esters. Moreover, DFMO did not antagonize induction of adhesion or IL-1 beta mRNA expression by TNF. Thus, polyamine biosynthesis plays an important role in priming by TNF, but is not involved in all PMN responses to this cytokine. This suggests that ODC is a potential target for selective chemotherapeutic modulation of the inflammatory response.
Section of Periodontology, College of Dentistry, Ohio State University Health Sciences Center, Columbus 43210.
J D
JD
Walters
A C
AC
Cario
B
B
Leblebicioglu
M C
MC
Fernandez
P T
PT
Marucha
D002448:Cell Adhesion / Q000187:drug effects; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism; D000518:Eflornithine / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D065108:Ornithine Decarboxylase Inhibitors; D010084:Oxidation-Reduction; D011700:Putrescine / Q000096:biosynthesis* / Q000097:blood*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects; D016897:Respiratory Burst / Q000187:drug effects; D012636:Secretory Rate / Q000187:drug effects; D013096:Spermine / Q000096:biosynthesis* / Q000097:blood*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D007375:Interleukin-1; D065108:Ornithine Decarboxylase Inhibitors; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D013096:Spermine; D011700:Putrescine; D000518:Eflornithine