PROSTACYCLIN AND PROSTAGLANDIN E-2 INHIBIT PROINFLAMMATORY CYTOKINE-INDUCED MACROPHAGE-COLONY-STIMULATING FACTOR PRODUCTION IN CULTURED HUMAN GLOMERULAR MESANGIAL CELLS

Monocyte/macrophages within the mesangium plays some important roles i n the progression of renal glomerular injury in which prostanoids exer t a broad range of actions. We have examined the production of macroph age colony-stimulating factor (M-CSF), a monocyte-specific cytokine, b y human glomerular mesangial cells (MC) and its regulation by prostacy clin and prostaglandin E-2 (PGE(2)). The M-CSF production by MC under non-stimulatory conditions was below detectable levels by ELISA, and w as also at a trace level in the steady-state M-CSF mRNA expression. Pr oinflammatory cytokines, interleukin-1 beta (IL-1 beta) or tumour necr osis factor-alpha (TNF-alpha) induced the M-CSF production in the prot ein and mRNA levels. Both beraprost, a stable analogue of prostacyclin , and PGE(2) attenuated the IL-1 beta- or TNF-alpha-driven M-CSF produ ction. Indomethacin, a non-selective cyclooxygenase inhibitor, enhance d the IL-1 beta- or TNF-alpha-induced M-CSF production. Beraprost and PGE(2) showed similar inhibitory effects in the presence of indomethac in. Forskolin, a direct activator of adenylate cyclase, and dibutyryl cAMP decreased the M-CSF production. These results indicate that: (i) human MC have capacity to produce M-CSF; (ii) exogenous prostacyclin a nd PGE(2) downregulate the IL-1 beta- or TNF-alpha-driven M-CSF produc tion possibly by an increase of intracellular cAMP; and (iii) endogeno us prostanoids can exert on the M-CSF production.