No abstract

The purpose of this investigation was to compare expression of genes that function in inflammation and stress, cell structure and signaling, or remodeling and growth in skeletal muscle of young (32 ± 7 yr, n = 15) and elderly (72 ± 5 yr, n = 16) healthy subjects before and after a bout of resistance leg exercises. A real-time RT-PCR method was used to screen 100 transcripts in v. lateralis biopsies obtained before and 72 h postexercise. The screen identified 15 candidates for differential expression due to aging and/or exercise that were measured quantitatively. The median levels of four mRNAs (insulin-like growth factor-1 and its binding protein IGFBP5, ciliary neurotrophic factor, and the metallopeptidase MMP2) were significantly affected by aging and were greater (1.6- to 2.3-fold, P ≤ 0.05) in the young than elderly muscle at both time points. The median levels of three mRNAs were significantly ( P ≤ 0.05) affected by exercise in the young. The metallopeptidase inhibitor TIMP1 and α-cardiac actin mRNAs increased 2-fold and 6.5-fold, respectively, and GDF8 (myostatin) mRNA decreased by 50%. However, elderly muscle did not display any significant changes in gene expression postexercise. Thus, aging muscle shows decreased levels at rest and an impaired response to exercise for a number of mRNAs for factors potentially involved in muscle growth and remodeling. Future studies must determine the functional importance of these gene expression changes to protein synthesis, satellite cell activity, and other processes that are directly involved in the mechanisms of muscle hypertrophy.

Sjögren's syndrome (SS) is a common autoimmune disease targeting salivary and lacrimal glands. It is strongly female-dominant, characterized by low oestrogen levels combined with a local intracrine dihydrotestosterone defect. We hypothesized that these hormonal deficits lead to increased apoptosis of the epithelial cells and plasmacytoid dendritic cell (pDC)-mediated proinflammatory host responses. Expression of Toll-like receptors (TLRs)-7 and -9 and cytokine profiles was studied in pDCs treated with apoptotic particles collected in consecutive centrifugation steps of media from apoptotic cells. Expression and localization of SS autoantigens in these particles was also analysed. Furthermore, the effects of sex steroids were studied in pDCs cultured with several concentrations of dihydrotestosterone and 17-β-oestradiol, and in saliva of patient treated with dehydroepiandrosterone. Apoptosis of the epithelial cells led to cleavage and translocation of SS-autoantigens, α-fodrin and SS-A, into apoptotic particles. The apoptosis-induced apoptotic particles also contained another SS-autoantigen, hy1-RNA. These particles were internalized by pDCs in a size-dependent manner and affected TLR-7 and -9 expression and the production of proinflammatory cytokines. The analysed androgens protected cells from apoptosis, influenced redistribution of autoantigens and diminished the apoptotic particle-stimulated increase of the TLRs in pDCs. Our findings suggest that the formation of apoptotic particles may play a role in loss of immune tolerance, manifested by production of autoantibodies and the onset of autoinflammation in SS.

Exposure to the environmental pollutant trichloroethylene (TCE) has been linked to autoimmune disease development in humans. Chronic (32-week) low-level exposure to TCE has been shown to promote autoimmune hepatitis in association with CD4(+) T cell activation in autoimmune-prone MRL+/+ mice. MRL+/+ mice are usually thought of as a model of systemic lupus rather than an organ-specific disease such as autoimmune hepatitis. Consequently, the present study examined gene expression and metabolites to delineate the liver events that skewed the autoimmune response toward that organ in TCE-treated mice. Female MRL+/+ mice were treated with 0.5 mg/mL TCE in their drinking water. The results showed that TCE-induced autoimmune hepatitis could be detected in as little as 26 weeks. TCE exposure also generated a time-dependent increase in the number of antibodies specific for liver proteins. The gene expression correlated with the metabolite analysis to show that TCE upregulated the methionine/homocysteine pathway in the liver after 26 weeks of exposure. The results also showed that TCE exposure altered the expression of selective hepatic genes associated with immunity and inflammation. On the basis of these results, future mechanistic studies will focus on how alterations in genes associated with immunity and inflammation, in conjunction with protein alterations in the liver, promote liver immunogenicity in TCE-treated MRL+/+ mice.