INDUCTION OF MESANGIAL INTERLEUKIN-6 SYNTHESIS BY APOPTOTIC U937 CELLS AND MONOCYTES

Infiltration of the glomerular mesangium by monocytes and macrophages is a central pathologic feature in various forms of glomerulonephritis . Dependent on the presence and activity of local survival factors, mo nocytes may undergo apoptosis. Therefore, we looked for the interactio n between cultured human mesangial cells (HMC) and intact, necrotic or apoptotic monocytic cells with different stages of programmed cell de ath (U937 cells and blood-derived human monocytes) and the possible ev oked secretory responses of HMC. Interleukin-6 (IL-6) synthesis of HMC after a two hour co-culture with late apoptotic U937 cells was signif icantly increased (505 +/- 55 pg/ml), and was further elevated after 2 0 hours (815 +/- 108 pg/ml). U937 cells alone, after incubation in HMC -conditioned medium or after coincubation with HMC, did not produce an y detectable IL-6. A high mesangial IL-6 synthesis in response to apop totic U937 cells was dependent on the cellular contact between HMC and U937 and could not be mimicked by apoptotic U937 culture supernatants . Radiolabeling studies indicated that HMC bound (16.6 +/- 2.4%) and i ngested (12.5 +/- 1.9%) apoptotic U937 cells to a much higher amount a s compared to intact U937 (5.3 +/- 2.0% binding; 5.0 +/- 1.1% phagocyt osis). Binding and ingestion of monocytic cells undergoing apoptosis w as confirmed by morphologic studies using electron microscopy. Incubat ion of HMC with a blocker of the CD36 vitronectin receptor (VnR) depen dent recognition mechanism of phagocytes for apoptotic leukocytes (RGD S peptide) did not alter binding, phagocytosis of IL-6 synthesis of HM C in response to apoptotic U937 Phospho-L-serine as an antagonist of t he phosphatidylserine (PS) mediated recognition pathway for apoptotic cell disposal was able to reduce binding and IL-6 production by HMC bu t not phagocytosis. Thus, binding of apoptotic monocytic cells by HMC rather than ingestion may be the binding and phagocytosis of particles in general might stimulate HMC to produce IL-6, we looked for mesangi al IL-6 production after binding and ingestion of opsonized zymosan pa rticles. In this case, IL-6 synthesis was markedly down-regulated. Fur thermore, HMC proliferated after zymosan treatment, whereas after apop totic cell uptake the mesangial cell number remained constant. In conc lusion, apoptotic monocytic cells provoked an enhanced mesangial IL-6 synthesis by a PS-dependent recognition mechanism. this secretory resp onse may have secondary implications for humoral or cellular processes within the mesangium.