Induced expression of serum amyloid A (SAA) is a hallmark of many inflammatory diseases, but whether SAA exacerbates inflammation or protects tissues against injury remains unclear. In dextran sulfate sodium (DSS)-induced colitis, SAA3 is the predominant isoform of inducible SAA proteins that also include SAA1 and SAA2, and mice with genetic deletion of Saa3 exhibits increased production of proinflammatory cytokines, decreased expression of IL-22 along with aggravated epithelium disruption, and reduced colon length compared with wild-type littermates. Colonic neutrophils have been identified as a major source of IL-22 in these mice. Administration of exogenous SAA3 as recombinant protein to Saa3−/− mice improves neutrophil IL-22 production, colonic epithelial integrity, and secretion of the antimicrobial peptides Reg3β and Reg3γ. Stimulation of mouse bone marrow neutrophils with mouse SAA3 or human SAA1 leads to expansion of IL-22-producing neutrophils. Unlike previously reported IL-22 induction through IL-23, the SAA3-induced neutrophil IL-22 expression utilizes a TLR2-dependent mechanism that does not depend on IL-23. Adoptive transfer of the SAA3-treated neutrophils to Saa3−/− mice ameliorates DSS-induced colitis and improves colonic epithelial integrity. These findings suggest that in the DSS-induced mouse colitis model, SAA isoforms are expressed to different extent in colon and deletion of Saa3 renders these mice more susceptible to DSS-induced injury. The presence of SAA3 in the inflamed colon mucosal serves to protect epithelial barrier in part through expansion of IL-22-producing neutrophils. It is speculated that SAA3 stimulation of autologous neutrophils may have therapeutic potential for inflammatory bowel disease.

Sphingomyelin synthase 1 (SMS1) and SMS2 are two isoforms of SMS, the last enzyme for sphingomyelin (SM) biosynthesis. To evaluate the role of SMS in vivo in terms of plasma lipoprotein metabolism, we generated recombinant adenovirus vectors containing human SMS1 cDNA (AdV-SMS1), SMS2 cDNA (AdV-SMS2), or the reporter LacZ cDNA (AdV-LacZ) as a control. On day 7 after intravenous infusion of 2 3 10 11 particles of both AdV-SMS1 and AdV-SMS2 into mice, liver SMS1 and SMS2 mRNA levels as well as SMS activity were significantly increased (2.5-, 2.7-, 2.1-, and 2.3-fold, respectively; P , 0.001). Lipoprotein analysis indicated that AdV-SMS1 and AdV-SMS2 treatment caused no changes of total SM and cholesterol levels but significantly decreased HDL-SM and HDL-cholesterol (42% and 38%, and 27% and 25%, respectively; P , 0.05). It also significantly increased non-HDL-SM and non-HDLcholesterol levels (50% and 35%, and 64% and 61%, respectively; P , 0.05) compared with AdV-LacZ controls. SDS--PAGE showed a significant increase in apolipoprotein B (apoB; P , 0.01) but no changes in apoA-I levels. Moreover, we found that non-HDL from both AdV-SMS1-and AdV-SMS2-treated mice was significantly aggregated after treatment with a mammalian sphingomyelinase, whereas lipoproteins from control animals did not aggregate. To investigate the mechanism of HDL changes, we measured liver scavenger receptor class B type I (SR-BI) levels by Western blot. We found that AdV-SMS1 and AdV-SMS2 mouse liver homogenates contained 50% and 55% higher SR-BI levels than in controls, whereas no change was observed in hepatic ABCA1 levels. An HDL turnover study revealed an increase of plasma clearance rates for ]HDL in both AdV-SMS1 and AdV-SMS2 mice compared with controls. In conclusion, adenovirus-mediated SMS1 and SMS2 overexpression increased lipoprotein atherogenic potential. Such an effect may contribute to the increased plasma SM levels observed in animal models of atherosclerosis and in human patients with coronary artery disease.-Dong, J., J.

Although studies have shown that di(2-ethylhexyl) phthalate (DEHP) can disrupt ovarian function, few reports have focused on follicular development in mice between the weaning period and maturity, especially with respect to microRNA (miRNA) expression. In this study, 21-day-old ICR mice were administered DEHP at doses of 0, 100, 400, and 1600 mg/(kg d) for 6 weeks by gavage. After DEHP administration, a significant decrease in the expression of follicle development-related factors (including c-kit, kitl, gdf9, and atm) was observed by quantitative real-time PCR (RT-PCR), but no significant difference in the proteins encoded by these genes was observed by Western blot. Bisulfite sequencing suggested that the total methylation percentages of promoter regions of these genes were not notably altered after DEHP exposure. However, RT-PCR revealed a significantly increased expression of ovarian miRNAs (let-7b, miR-17-5p miR-181a, and miR-151), which inhibit follicular granulosa cell proliferation. Overall, this study showed that DEHP administration from weaning to maturity could suppress the mRNA expression of follicular development factors, and this effect was not achieved through changes in the methylation of DNA in CpG islands of development factors. In addition, DEHP was shown to induce miRNAs to inhibit the proliferation of follicular granulosa cells and the anti-apoptosis function of KITL and GDF9 while increasing bax/bcl expression to further promote the apoptosis of granulosa cells.

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