Alpha‐ and gamma‐interferon (IFNα, IFNγ) but not interleukin‐1 (IL‐1) modulate synthesis and secretion of β2‐microglobulin by hepatocytes

Abstract

Soluble serum beta 2-microglobulin has been thought to result from membrane shedding by activated T-lymphocytes. This hypothesis could explain the increase of beta 2-microglobulin serum levels during virally induced mononucleosis, but not elevated levels as observed in other virally induced and in malignant diseases. In this paper we demonstrate that beta 2-microglobulin is a true secretory protein, and that its synthesis in hepatocytes is modulated by IFNs but not by IL-1. While the 45,000 MW HLA antigen can be found only in cell lysates, beta 2-microglobulin is shown to be secreted also into the culture medium like other secretory proteins (e.g. albumin-factor B-complement C3). Furthermore, interferon alpha (IFN alpha) as well as interferon gamma (IFN gamma) directly stimulate, in a dose- and time-dependent manner, beta 2-microglobulin synthesis by human hepatoma cells (Mz-Hep-1 and PLC/PRF5) and murine hepatocyte primary cultures. The increase of beta 2-microglobulin production induced by interferons is demonstrated at both the protein and the RNA level, indicating that interferon acts at a pretranslational level. The interferon effect on beta 2-microglobulin synthesis is specific since synthesis of secretory proteins like complement C3 or albumin, and of a structural protein like actin, remains unchanged. In contrast to IFN, IL-1, the main mediator of acute phase response, does not change beta 2-M biosynthesis rate. These data indicate that (i) beta 2-microglobulin is a secretory protein, (ii) IFNs but not IL-1 can mediate increased beta 2-M serum levels, and (iii) the liver may be its primary source.