RA patients treated with TCZ show lower plasma concentrations of Lp(a) compared with patients without BT.
In the rat oviduct, estradiol (E2) accelerates egg transport by a nongenomic action that requires previous conversion of E2 to methoxyestrogens via catechol-O-methyltranferase (COMT) and activation of estrogen receptor (ER) with subsequent production of cAMP and inositol triphosphate (IP3). However, the role of the different oviductal cellular phenotypes on this E2 nongenomic pathway remains undetermined. The aim of this study was to investigate the effect of E2 on the levels of cAMP and IP3 in primary cultures of secretory and smooth muscle cells from rat oviducts and determine the mechanism by which E2 increases cAMP in the secretory cells. In the secretory cells, E2 increased cAMP but not IP3, while in the smooth muscle cells E2 decreased cAMP and increased IP3. Suppression of protein synthesis by actinomycin D did not prevent the E2-induced cAMP increase, but this was blocked by the ER antagonist ICI 182 780 and the inhibitors of COMT OR 486, G protein-α inhibitory (Gαi) protein pertussis toxin and adenylyl cyclase (AC) SQ 22536. Expression of the mRNA for the enzymes that metabolizes estrogens, Comt, Cyp1a1, and Cyp1b1 was found in the secretory cells, but this was not affected by E2. Finally, confocal immunofluorescence analysis showed that E2 induced colocalization between ESR1 (ERα) and Gαi in extranuclear regions of the secretory cells. We conclude that E2 differentially regulates cAMP and IP3 in the secretory and smooth muscle cells of the rat oviduct. In the secretory cells, E2 increases cAMP via a nongenomic action that requires activation of COMT and ER, coupling between ESR1 and Gαi, and stimulation of AC.
Mating shuts down a 2-methoxyestradiol (2ME)-dependent, non-genomic activity that is responsible for accelerating egg transport in the rat oviduct. The aims of this work were to investigate the role of TGFβ1 in this 2ME-reduced activity and to determine the effect of mating on the expression and distribution of TGFβ1 and its receptor TGFBR3 in the rat oviduct. We determined the level of TGFβ1 in the plasma and oviductal fluid at 1, 3, or 6 hr during Day 1 of the oestrous cycle in unmated or mated animals. We then examined if 2ME accelerates oviductal egg transport in unmated rats that were previously treated with a neutralizing TGFβ1 antibody. The expression of Tgfb1 and Tgfbr3 mRNA and the level and distribution of TGFBR3 protein in the oviduct were also determined at these time points. Mating decreased TGFβ1 in the plasma, but not in the oviductal fluid, whereas antibody neutralization of circulating TGFβ1 did not prevent the effect of 2ME on egg transport. Mating decreased Tgfb1 and hastened the increase in TGFBR3 abundance in the myosalpinx. These results indicate that mating decreased circulating levels of TGFβ1 without shutting down the non-genomic 2ME response that normally accelerates egg transport. Levels of Tgfb1 transcript and TGFBR3 protein, however, changed in the myosalpinx of mated rats, suggesting a role for mating-associated factors in the autocrine and paracrine effects of TGFβ in the oviduct.
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