COMPARATIVE EXPRESSION OF TNF-ALPHA ALLELES FROM NORMAL AND AUTOIMMUNE-PRONE MHC HAPLOTYPES

The tumor necrosis factor-alpha (TNF-alpha, or TNF) genes of NOD mice and NZW mice are reportedly underexpressed relative to the TNF genes o f control mice in lipopolysaccharide (LPS)-induced peritoneal macropha ges. These findings, as well as the well-known major histocompatibilit y complex (MHC) linkage of the TNF genes, have prompted speculation th at mutations affecting expression of the TNF-alpha loci might represen t a primary cause of autoimmune diseases. Differences in expression of the TNF genes in different strains of mice might result either from e ffects of cis-acting mutations or from differences in the cellular env ironment that operate in trans. To discriminate between these possibil ities, we directly examined the relative contribution made by each of two different TNF alleles (one associated with an autoimmune-prone hap lotype and the other not) to the pool of TNF mRNA within the cells off , hybrid mice. Reverse transcription-polymerase chain reaction (RT-PCR ) was used to amplify a polymorphic fragment derived from the total po ol of TNF mRNA present in LPS-induced peritoneal macrophages of hybrid animals produced by crossing BALB/c to non-obese diabetic (NOD), and New Zealand black (NZB) to New Zealand white (NZW). In both types of F -1 hybrid, the two alleles were represented in nearly equal quantities at the mRNA level. It may be inferred that at all pretranslational le vels, the NZW and NOD TNF alleles are functionally equivalent to the c ontrol alleles that were examined. Interstrain differences in responsi veness to LPS are therefore responsible for interstrain differences in TNF gene expression. (C) 1995 Wiley-Liss, Inc.