DOWN-REGULATION OF CYCLOOXYGENASE-2 (COX-2) BY INTERLEUKIN-1 RECEPTORANTAGONIST IN HUMAN MONOCYTES

Cyclooxygenase (COX) is the key rate-limiting enzyme in the synthesis of prostanoids from arachidonic acid. Two isoforms of COX have been de scribed in mammalian cells, referred to as cyclooxygenase-1 (COX-1) an d cyclooxygenase-2 (COX-2). COX-1 is a constitutively expressed enzyme ; COX-2 is an inducible enzyme that appears to be expressed in inflame d tissue and following exposure to growth factors or cytokines, such a s interleukin-1 (IL-1). The aim of the present study was to test if th e antagonism on the binding of IL-1 to its cell-surface receptor by hu man recombinant IL-1 receptor antagonist (hrIL-1ra) may control the CO X mRNA expression and prostaglandin E(2) (PGE(2)) production by human monocyte cultures. Northern blot studies showed that hrIL-ra (500 ng/m l) had a strong inhibitory effect on inducible COX activity. The effec t was evident after 6 hr incubation (2.7-fold decrease of mRNA COX-2 t ranscripts): and about a threefold decrease at 24 hr incubation, A non -significant effect was observed with COX-1 transcripts. Induced PGE(2 ) production by monocyte cultures treated with lipopolysaccharide (LPS ) or interleukin-1 beta (IL-1 beta) was strongly inhibited in the pres ence of hrIL-1ra (500 ng/ml). In addition, a significant inhibition of COX-2 protein expression, as evaluated by Western blotting, was also observed. These data suggest that hrIL-1ra may be the key mediator in the downregulation of the COX-2 inducible pathway.