GENETIC-CONTROL OF IN-VIVO TUMOR-NECROSIS-FACTOR PRODUCTION IN MICE

We report on the genetic effect on in vivo production of tumor necrosi s factor (TNF)-alpha induced by lipopolysaccharides (LPS) using variou s congenic mouse strains. B10.A, B10.A(3R), B10.AQR, B10.A(5R), and B1 0.S(7R) produced significantly high TNF-alpha compared with B10.BR, B1 0.S, C57BL/10, B10.A(2R), B10.A(4R), B10.G, B10.DA(80NS), and B10.RIII (71NS). This suggests that LPS-induced TNF-alpha production is genetic ally controlled by H-2. Mice with the same alleles on K, A, E, or S lo ci produced various (high or low) levels of TNF-alpha, thus indicating that regulatory genes are located outside these loci. Ail strains wit h H-2D(d) produced significantly high levels of TNF-alpha, but strains with other alleles in the H-2D locus produced low levels. Thus, TNF-a lpha production appears to be genetically linked to H-2D itself or H-2 D linked genes and the allele d is linked to a high responder gene. Th is was the case with the A background. C3H/HeN (H-2(k)), however, show ed a high TNF-alpha production, suggesting the presence of another con trolling gene outside H-2. In addition, high TNF-alpha productivity wa s transmitted into F1 mice (B10.A x B10.BR) in a dominant fashion. Bot h LPS-stimulated and unstimulated TNF-alpha mRNA expression in splenic macrophages were enhanced in high responder strains. Thus, we conclud e that TNF-alpha production is closely related to genes within or link ed to the H-2D locus as well as others outside H-2. (C) 1996 Academic Press, Inc.