OSMOTIC REGULATION OF CYTOKINE SYNTHESIS IN-VITRO

These studies were undertaken to investigate the therapeutic mechanism of saturated solution of KI, used to treat infectious and inflammator y diseases. The addition of 12-50 mM KI to cultured human peripheral b lood mononuclear cells resulted in 319-395 mosM final solute concentra tion and induced interleukin (IL)-8 synthesis. Maximal IL-8 production was seen when 40 mM salt was added (375 mosM) and was equal to IL-8 i nduced by endotoxin of IL-1 alpha. However, there was no induction of IL-1 alpha, IL-1 beta, or tumor necrosis factor to account for the syn thesis of IL-8; the effect of KI was not due to contaminating endotoxi ns. Hyperosmolar NaCl also induced IL-8 and increased steady-state lev els of IL-8 mRNA similar to those induced by IL-1 alpha. IL-8 gene exp ression was elevated for 96 hr in peripheral blood mononuclear cells i ncubated with hyperosmolar NaCl. In human THP-1 macrophagic cells, osm otic stimulation with KI, NaI, or NaCl also induced IL-8 production. I L-1 signal transduction includes the phosphorylation of the p38 mitoge n-activated protein kinase that is observed following osmotic stress. Using specific blockade of this kinase, a dose-response inhibition of hyperosmolar NaCl-induced IL-1. Thus, these studies suggest that IL-1 and osmotic shock utilize the same mitogen-activated protein kinase fo r signal transduction and IL-8 synthesis.