Gender- and androgen-related influence on the expression of proto-oncogene and apoptotic factor mRNAs in lacrimal glands of autoimmune and non-autoimmune mice.
Our previous studies have shown that the mRNA levels of c-myb, c-myc, bcl-2 and p53 are higher, and partial Fas antigen (i.e. exons 1-2) lower, in lacrimal tissues of female, as compared to male, MRL/lpr mice, which are a model of Sjögren's syndrome. We have also found that this gender-related difference in bcl-2 and c-myb expression appears to be due to the influence of androgens. To extend these findings, we sought to determine: first, whether these gender- and/or hormone-associated variations in mRNA content are unique to MRL/lpr mice, or are also present in lacrimal glands of other murine strains, including autoimmune NZB/NZW F1 (F1) and non-obese diabetic (NOD), as well as non-autoimmune C3H/HeJ (C3H) and BALB/c, mice; and second, whether the levels of these apoptotic factor mRNAs are altered in lacrimal tissues of mice (i.e. testicular feminized (Tfm) with dysfunctional androgen receptors, as compared to glandular amounts in their 'normal' controls (i.e. Tabby). Lacrimal tissues were obtained from adult mice, which were either untreated or treated with placebo or testosterone for 21 days. Glands were processed for the analysis of proto-oncogene mRNAs by RT-PCR (at exponential phase of amplification) and data were standardized to the corresponding levels of beta-actin mRNA. Our results demonstrate that Fas antigen, Fas ligand, c-myb, c-myc, bcl-2, Bax and p53 mRNAs are present in lacrimal tissues of F1, NOD, C3H, BALB/c, Tabby and Tfm mice. The relative levels of Fas antigen mRNA are consistently higher in glands of males, whereas amounts of bcl-2 mRNA are greater in tissues of F1, C3H and BALB/c females. Testosterone administration induced a significant increase in the lacrimal gland content of Bax mRNA, but a striking decrease in the lacrimal tissue level of bcl-2 mRNA in F1 and C3H mice. Lacrimal glands of Tfm mice contained elevated amounts of bcl-2 mRNA, as compared to values in tissues of their Tabby controls. In summary, our findings show that fundamental gender-related differences exist in the expression of genes associated with programmed cell death in lacrimal glands of autoimmune and normal mice. In addition, some of these differences may be due, at least in part, to the effect of androgens.
Toda
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I
Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
Sullivan
B D
BD
Wickham
L A
LA
Sullivan
D A
DA
D000728:Androgens / Q000378:metabolism*; D000818:Animals; D001327:Autoimmune Diseases / Q000378:metabolism*; D053222:Fas Ligand Protein; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D020570:Genes, myb; D007765:Lacrimal Apparatus / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D019463:Mice, Inbred MRL lpr; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000235:genetics; D011519:Proto-Oncogenes / Q000235:genetics*; D012333:RNA, Messenger; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D013739:Testosterone / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000187:drug effects / Q000235:genetics*
D000728:Androgens; C494827:Bax protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011944:Receptors, Androgen; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D013739:Testosterone