Interleukin-12p35 Deficiency Reverses the Th1/Th2 Imbalance, Aggravates the Th17/Treg Imbalance, and Ameliorates Atherosclerosis in ApoE-/- Mice

Interleukin- (IL-) 35, a novel functional cytokine of regulatory T cells (Treg) comprised of the IL-12p35 subunit and the other subunit Epstein-Barr virus-induced gene 3 (EBI3), regulates the activity of CD4+ T cells and macrophages, thereby playing a critical role in inflammatory and autoimmune diseases. Previous studies demonstrated that both recombinant mice and human IL-35 attenuated atherosclerosis in ApoE-/- mice. Additionally, EBI3 deficiency enhanced the activation of macrophages and increased atherosclerotic lesions in LDLR-/- mice. This study generated double-deficient mice for ApoE and IL-12p35 (ApoE-/- IL-12p35-/- mice) and investigated the effect of IL-12p35 deficiency on atherosclerosis. IL-12p35 deficiency alleviated Th1/Th2 imbalance, aggravated Th17/Treg imbalance, and attenuated atherosclerotic plaque formation in ApoE-/- mice. Additionally, exogenous rIL-35 treatment reversed the imbalance of Th17/Treg and attenuated atherosclerosis in ApoE-/- mice. These findings suggest that IL-12p35 deficiency ameliorates atherosclerosis in ApoE-/- mice, partially, via attenuating the Th1/Th2 imbalance, although IL-12p35 deficiency aggravates the Th17/Treg imbalance.

Periodic breathing in the mouse

The hypothesis was that unstable breathing might be triggered by a brief hypoxia challenge in C57BL/6J (B6) mice, which in contrast to A/J mice are known not to exhibit short-term potentiation; as a consequence, instability of ventilatory behavior could be inherited through genetic mechanisms. Recordings of ventilatory behavior by the plethsmography method were made when unanesthetized B6 or A/J animals were reoxygenated with 100% O2 or air after exposure to 8% O2 or 3% CO2-10% O2 gas mixtures. Second, we examined the ventilatory behavior after termination of poikilocapnic hypoxia stimuli in recombinant inbred strains derived from B6 and A/J animals. Periodic breathing (PB) was defined as clustered breathing with either waxing and waning of ventilation or recurrent end-expiratory pauses (apnea) of ≥2 average breath durations, each pattern being repeated with a cycle number ≥3. With the abrupt return to room air from 8% O2, 100% of the 10 B6 mice exhibited PB. Among them, five showed breathing oscillations with apnea, but none of the 10 A/J mice exhibited cyclic oscillations of breathing. When the animals were reoxygenated after 3% CO2-10% O2 challenge, no PB was observed in A/J mice, whereas conditions still induced PB in B6 mice. (During 100% O2 reoxygenation, all 10 B6 mice had PB with apnea.) Expression of PB occurred in some but not all recombinant mice and was not associated with the pattern of breathing at rest. We conclude that differences in expression of PB between these strains indicate that genetic influences strongly affect the stability of ventilation in the mouse.

Fine Mapping of the Friend Retrovirus Resistance Gene, Rfv3, on Mouse Chromosome 15

ABSTRACT Rfv3 is a host resistance gene that operates through an unknown mechanism to control the development of the virus-neutralizing antibody response required for recovery from infection with Friend retrovirus. The Rfv3 gene was previously mapped to an approximately 20-centimorgan (cM) region of chromosome 15. More refined mapping was not possible, due to a lack of microsatellite markers and leakiness in the Rfv3 phenotype, which prevented definitive phenotyping of individual recombinant mice. In the present study, we overcame these difficulties by taking advantage of seven new microsatellite markers in the Rfv3 region and by using progeny tests to accurately determine the Rfv3 phenotype of recombinant mice. Detailed linkage analysis of relevant crossovers narrowed the location of Rfv3 to a 0.83-cM region. Mapping of closely linked genes in an interspecific backcross panel allowed us to exclude two previous candidate genes, Ly6 andWnt7b. These studies also showed for the first time that the Hsf1 gene maps to the Rfv3-linked cluster of genes including Il2rb, Il3rb, and Pdgfb. This localization of Rfv3 to a region of less than 1 cM now makes it feasible to attempt the cloning of Rfv3 by physical methods.

I-E-linked control of spontaneous rheumatoid factor production in normal mice.

The concentration of serum IgM molecules binding to IgG2a (rheumatoid factor [RF]) in solid phase assays is 10-100-fold higher in normal, unmanipulated C3H/HeJ (H-2k) than in C57BL/6 (H-2b) mice. Analysis of MHC-congenic mice with the prototype strains show that C3H SW (H-2b) are low, and B6.H-2k are high RF expressor strains, respectively. Furthermore, segregation of RF phenotypes in progenies from backcrosses to C3H/HeJ of (C3H/HeJ x C57BL/6)F1 hybrid mice shows MHC- and IgH-linked controls. RF phenotypes also segregate as if they are MHC linked in crosses between H-2-congenic strains (C3H/HeJ and C3H.SW). The study of intra-H-2 (k/b and k/s) recombinant mice suggested that RF phenotype control is linked to the I-E region. This was confirmed by the typing of C57BL/6 mice expressing a transgenic E alpha chain, and thus, I-E+, which, in contrast to nontransgenic littermates, are high expressors of RF.