Abstract
Although many neurological and psychiatric disorders reveal clear sex-dependent variations, the molecular mechanism of this process is not clear enough. Astrocytes are involved in the response of neural tissue to injury and inflammation, produce steroid hormones, and sense steroid presence. To explore the hypothesis that astrocytes may participate in sex-mediated differences of inflammatory responses, we have examined whether male and female primary rat astrocytes show different responses to lipopolysaccharide (LPS) as a toll-like receptor 4 (TLR4) agonist. Levels of mRNA and proteins of tumor necrosis factor alpha (TNFα), interleukin-10 (IL-10), and cyclooxygenase (COX)-2 were assessed using qPCR, immunoblotting, and ELISA. UPLC-MS/MS was used to detect prostaglandins (PGs). LPS stimulation resulted in different levels of cytokine production; more TNFα and less IL-10 were produced in female cells compared with male astrocytes. Although the levels of the COX-2 expression were not altered, LPS significantly induced the synthesis of PGs with notable sex-related differences. PGE2 and PGD2 were less and 6-keto-PGF1α was more upregulated in female astrocytes, and TXB2 had similar levels in cells obtained from males and females. Trilostane, an inhibitor of 3β-Hydroxysteroid dehydrogenase (3β-HSD), inhibited the LPS-induced TNFα production and the release of PGE2, PGD2, and 6-keto-PGF1α in female astrocytes. Thus, male and female astrocytes differentially respond to inflammatory challenges on the level of production of cytokines and steroid hormones. Sex-mediated differences in pro- and anti-inflammatory responses should be taken into consideration for the effective treatment of disorders with neuroinflammation.
Highlights
Sex-dependent variation in the sensitivity of humans to some diseases has been known for a long time, in experimental and clinical studies, the sex of subjects is still rarely taken into account
The obtained results indicate that the primary astrocytes derived from male and female rat pups show a different expression of a pro-inflammatory marker TNFα and prostaglandins, as well as expression of an of an anti-inflammatory marker IL-10 in response to LPS
Astrocytes Isolated from Male or Female Pups Reveal Similar Morphology, But Demonstrate Differences ainntRi-einspfloanmsems taotoLrPySmarker IL-10 in response to LPS
Summary
Sex-dependent variation in the sensitivity of humans to some diseases has been known for a long time (see for reviews [1,2,3,4]), in experimental and clinical studies, the sex of subjects is still rarely taken into account. The modulation of the cyclooxygenase (COX)-2 expression by LPS induces synthesis of various prostaglandins (PG) [17,18], which, modifies both the pro-inflammatory and anti-inflammatory processes, depending on the cellular context [19,20,21]. We hypothesized that the astrocyte obtained from male or female brains would have different levels of cytokines and prostaglandins in conditions with or without a pro-inflammatory challenge, and trilostane would have an anti-inflammatory effect that might reveal a sex-dependent variety. The obtained results indicate that the primary astrocytes derived from male and female rat pups show a different expression of a pro-inflammatory marker TNFα and prostaglandins, as well as expression of an of an anti-inflammatory marker IL-10 in response to LPS. Our data implies the possibility to use trilostane as a component of an anti-inflammatory therapy in female subjects
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
