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 associated with the local release of growth factors and various cytokines. In a previous study, we investigated the effect of various cytokines on triacylglycerol and apoB secretion by CaCo-2 cells and observed that TNF-alpha, IL-1 beta, and particularly IL-6, decreased apolipoprotein (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 cells grown on semi-permeable filters, decreased apoB secretion by 42%. Adding a blocking monoclonal antibody (mAb 528) to the EGF receptor completely prevented this effect. IL-6 decreased the amount of EGF receptor protein and the binding of iodinated EGF to its receptor by 50% and 30%, respectively. Incubation of cells with various ligands to the EGF receptor, such as EGF, TGF-alpha, HB-EGF, and amphiregulin, also decreased apoB secretion. Inhibition of apoB secretion by EGF was prevented by the mAb 528 or an EGF neutralizing antibody. In a dose-dependent manner, the neutralizing antibody to EGF prevented the decrease in secretion of apoB, triacylglycerol mass, and cell-surface binding of labeled EGF caused by IL-6. Similar to the effects of IL-6, EGF decreased the secretion of triacylglycerol mass and the synthesis and secretion on newly synthesized apoB. The results suggest that, in CaCo-2 cells, 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.
Murthy
S
S
Department of Internal Medicine, University of Iowa, Iowa City 52242, USA.
Mathur
S
S
Bishop
W P
WP
Field
E J
EJ
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D001055:Apolipoproteins B / Q000187:drug effects / Q000378:metabolism*; D001667:Binding, Competitive; D018938:Caco-2 Cells; D003432:Cross-Linking Reagents / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004815:Epidermal Growth Factor / Q000032:analysis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000031:analogs & derivatives / Q000494:pharmacology*; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007457:Iodine Radioisotopes; D008715:Methionine / Q000032:analysis / Q000378:metabolism; D011994:Recombinant Proteins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013388:Succinimides / Q000737:chemistry; D013462:Sulfur Radioisotopes; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D000911:Antibodies, Monoclonal; D001055:Apolipoproteins B; D003432:Cross-Linking Reagents; D015850:Interleukin-6; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins; D013388:Succinimides; D013462:Sulfur Radioisotopes; D014280:Triglycerides; D004815:Epidermal Growth Factor; D008715:Methionine; C035760:bis(sulfosuccinimidyl)suberate; D066246:ErbB Receptors