PARACRINE INTERACTION BETWEEN HEPATOCYTES AND MACROPHAGES AFTER EXTRATHYROIDAL PROTEOLYSIS OF THYROGLOBULIN

Thyroglobulin (Tg), the precursor of the thyroid hormones triiodothyro nine (T-3) and thyroxine (T-4), is known to derive from thyroid epithe lial cells. Part of Tg reaches the circulation as an intact molecule b y transcytosis across the epithelial wall of thyroid follicles. Circul ating Tg is a potential ligand for the asialoglycoprotein receptor of hepatocytes. In this report we show, however, that clearance of circul ating Tg occurred exclusively by endocytosis in liver macrophages, whe reas hepatocytes did not participate in this process. The biological s ignificance of this Tg uptake by the macrophages might consist in an i ncrease of thyroid hormones in close proximity to the macrophages, the reby affecting the hepatocyte metabolism. To test this hypothesis, co- cultures of hepatocytes and macrophages were incubated with Tg, which resulted in the release of thyroid hormones and in a significant incre ase in the activity of lipogenesis and of hepatocellular key enzymes o f the hexose monophosphate shunt. This effect of Tg could be mimicked by equivalent amounts of T-3 or T-4 exclusively in the co-cultures. Wh en hepatocytes were incubated with thyroid hormones in the absence of macrophages, no or only little effect was observed, indicating that th e interaction of macrophages and hepatocytes was a prerequisite for th e stimulation of the hepatocellular metabolism. We conclude that the p aracrine effect on HepG2 cells results from the degradation of Tg in J 774 cells. Apparently, this process is not confined to the release of thyroid hormones, but it requires the interaction of both cell types, possibly mediated by an additional, as yet unknown stimulus.