CRYSTAL-INDUCED NEUTROPHIL ACTIVATION .5. DIFFERENTIAL PRODUCTION OF BIOLOGICALLY-ACTIVE IL-1 AND IL-1 RECEPTOR ANTAGONIST

Neutrophils produce IL-1 when stimulated by monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals. Neutrophils also gene rate the IL-1R antagonist (IL-1Ra), especially when incubated with gra nulocyte-macrophage CSF (GM-CSF) or TNF-alpha. We studied the simultan eous expression of IL-1 and IL-1Ra by GM-CSF- or TNF-alpha-treated neu trophils activated by MSU or CPPD. Neutrophils incubated with GM-CSF o r TNF-alpha produced approximately 300 or 200 times more IL-1Ra than I L-1, respectively. Suboptimal concentrations of MSU or CPPD induced lo w amounts of IL-1 without affecting IL-1Ra. Interaction of GM-CSF- and TNF-alpha-treated neutrophils with MSU or CPPD up-regulated IL-1 whil e simultaneously down-regulating IL-1Ra. As a result, the bioactivity of IL-1 secreted was enhanced. Synergistic increases of IL-1 (but not IL-1Ra) mRNA levels were noted in GM-CSF- or TNF-alpha-treated neutrop hils exposed to CPPD. Treatment of neutrophils with colchicine before incubation with GM-CSF or TNF alpha, inhibited crystal-induced IL-1 by 50 to 55%, but failed to significantly affect IL-1Ra. The IL-1Ra to I L-1 ratio was significantly increased by 185 to 220%. These results de monstrate that IF-1 and IL-1Ra production by human neutrophils are dif ferentially regulated, that the combined presence of GM-CSF or TNF-alp ha and microcrystals favor the production of biologically active IL-1 over that of IL-1Ra, and that colchicine selectively inhibits IL-1 wit hout affecting IL-1Ra production.