INHIBITION OF APOLIPOPROTEIN-B SECRETION BY IL-6 IS MEDIATED BY EGF OR AN EGF-LIKE MOLECULE IN CACO-2 CELLS

Small intestinal mucosal inflammation observed in celiac disease is as sociated with the local release of growth factors and various cytokine s. In a previous study, we investigated the effects of various cytokin es on triacylglycerol and apoB secretion by CaCo-2 cells and observed that TNF-alpha, IL-1 beta, and particularly IL-6, decreased apolipopro tein (apo) B and triacylglycerol secretion. In this study, we explored possible mechanisms to explain the inhibitory effect of IL-6 on apoB secretion. IL-6, 10 ng/mL, added to the basolateral medium of CaCo-2 c ells grown on semi-permeable filters, decreased apoB secretion by 42%. Adding a blocking monoclonal antibody (mAb 528) to the EGF receptor c ompletely prevented this effect. IL-6 decreased the amount of EGF rece ptor protein and the binding of iodinated EGF to its receptor by 50% a nd 30%, respectively. Incubation of cells with various ligands to the EGF receptor, such as EGF, TGF-alpha, HB-EGF, and amphiregulin, also d ecreased apoB secretion. Inhibition of apoB secretion by EGF was preve nted by the mAb 528 or an EGF neutralizing antibody. In a dose-depende nt manner, the neutralizing antibody to EGF prevented the decrease in secretion of apoB, triacylglycerol mass, and cell-surface binding of l abeled EGF caused by IL-6. Similar to the effects of IL-6, EGF decreas ed the secretion of triacylglycerol mass and the synthesis and secreti on of newly synthesized apoB. The results suggest that, in CaCo-2 cell s, IL-6 causes the release of EGF or an EGF-like molecule. By binding to cell surface EGF receptors, the molecule then causes a decrease in triacylglycerol and apoB secretion.