No abstract

Southern blot analysis with a murine interferon-alpha2 (MuIFN-alpha2) cDNA probe revealed restriction fragment polymorphism of EcoRI- and HindIII-digested C57BL/6 and BALB/cDNA. The inheritance pattern of this polymorphism was examined using DNA from each of the seven recombinant inbred strains derived from C57BL/6 and BALB/c; the strain distribution pattern suggests linkage of INF-alpha genes to two histocompatibility loci on chromosome 4. Southern blot analysis of DNA from six bilinear congenic strains carrying different fragments of the BALB/c chromosome 4 on a C57BL/6 background showed linkage of IFN-alpha genes to the histocompatibility locus H-15. It can therefore be concluded that the IFN-alpha gene cluster is situated on chromosome 4 near the H-15 locus, between loci Mup-1 and b.

There are sexual differences in early (2-3 h) interferon (IFN) production induced by NDV in the mouse, in that circulating IFN levels are higher in females than in males. From a Mendelian analysis carried out in BALB/c and C57BL/6 mice, it can be concluded that early IFN levels are quantitatively influenced by an X-linked locus, with different alleles in C57BL/6 and BALB/c. As a result of these distinct alleles, the IFN levels of the male progeny of the reciprocal F1 crosses were significantly higher when the X-chromosome was of C57BL/6 origin than when it was of BALB/c origin. The difference in early IFN production between males and females is detectable after puberty only, which indicates that sexual maturation factors influence, in the male, the expression of the X-linked locus. These observations point to differences between early and late IFN production in response to NDV. As reported earlier, there is no effect of sex on late (6-9 h) IFN production, which is under the influence of the autosomal If-1 locus. The results presented here show that whereas late IFN production is very radiosensitive, early IFN production, on the contrary, is radioresistant, indicating that different cell populations are involved in early versus late IFN synthesis.

Mouse interferon inhibits proliferation of bone-marrow derived macrophages. The degree of inhibition of cell proliferation is significant influenced by the genotype of the bone marrow donor in that C57BL/6 cells are more resistant to the cell multiplication inhibitory effect of interferon than are BALB/c cells. These results thus confirm earlier observations using murine erythroid precursors as target cells and point to the existence of genes modulating the action of interferon.

BALB/c mice are more sensitive to the antiviral effect of interferon than C57BL/6 mice, as demonstrated by experiments involving protection against lethal infection with encephalomyocarditis virus. This greater sensitivity of the BALB/c genotype to interferon action is in accord with previous observations that the bone marrow-derived erythroid precursors and macrophages of BALB/c mice are more sensitive to the anti-proliferative action of interferon than those of C57BL/6 mice. An analysis of the loci involved in the modulation of the activity of interferon against encephalomyocarditis virus infection was carried out in (BALB/c x C57BL/6)F1 progeny and in six recombinant inbred lines originally derived from a BALB/c x C57BL/6 cross. The antiviral effect of exogenous interferon in the F1 progeny was comparable to the effect in BALB/c mice, indicating dominance of the greater sensitivity to interferon action. The results obtained with the six recombinant inbred lines suggested a multifactorial influence. In vitro, interferon pretreatment of encephalomyocarditis virus-infected BALB/c and C57BL/6 fibroblast cultures did not reveal a difference in sensitivity between the two mouse genotypes. This finding demonstrates that it is not always possible to extrapolate from in vitro to in vivo when sensitivity to interferon action is studied.