Negative correlation between testosterone and TNF-α in umbilical cord serum favors a weakened immune milieu in the human male fetoplacental unit. Issue 186 (February 2019)

• Record Type: Journal Article
• Authors: Olmos-Ortiz, Andrea; García-Quiroz, Janice; Halhali, Ali; Avila, Euclides; Zaga-Clavellina, Verónica; Chavira-Ramírez, Roberto; García-Becerra, Rocío; Caldiño-Soto, Felipe; Larrea, Fernando; Díaz, Lorenza
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 186(2019)
• Page Start: 154
• Page End: 160
• Publication Date: 2019-02
• Subjects: 25OHD3 25-hydroxyvitamin D3 -- CAMP human cathelicidin antimicrobial peptide -- VD vitamin D -- AMP antimicrobial peptide -- IL interleukin -- Th T helper -- TNF tumor necrosis factor -- hCG human chorionic gonadotropin -- HBD human β-defensins -- UC umbilical cord; TNF-α -- IL-1β -- Sexual dimorphism -- Placenta -- Calcitriol -- Vitamin D; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2018.10.009
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: Male placentas and cord serum show an immunosuppressive immune signature. Male neonates showed low umbilical serum TNF-α and high IL-10 levels and gene expression. IL-1β expression was stimulated by VD metabolites in cultured trophoblasts. Abstract: Clinical and epidemiological evidence supports that pregnancies carrying a male fetus are more vulnerable to infections and preterm birth, probably due to testosterone immunosuppressive properties. In human placentas, testosterone lowers the expression of CYP27B1, the vitamin D (VD)-activating enzyme, diminishing cathelicidin synthesis, a potent VD-dependent antimicrobial peptide (AMP). VD also stimulates other AMPs, including defensins. To get insights into the increased male vulnerability mechanisms, we investigated the relationship between fetal sex and the immunoendocrine milieu at the fetoplacental unit. For this, umbilical vein serum and placental samples were collected from healthy newborns. In males' serum, testosterone levels were significantly higher and negatively associated with TNF-α, a cytokine that strengthens the immune response. Males showed lower serum TNF-α and increased levels and gene expression of the immunosuppressive cytokine IL-10. Only in female samples there was a positive association ( P < 0.05) between AMPs and both TNF-α and CYP27B1 and between 25-hydroxyvitamin D3 and IL-1β serum levels. Accordingly, VD-metabolites (25-hydroxyvitamin D3, calcitriol) significantly stimulated IL-1β gene expression in cultured trophoblasts. Interestingly, IL-1β mRNA correlated positively with defensins ( P < 0.05) in males, but not with cathelicidin expression, which was significantly diminished in comparison to females. Our data suggest that high umbilical serum testosterone and IL-10 in males could explain reduced TNF-α levels and lack of association between VD-dependent innate immunity markers and proinflammatory cytokines expression in the fetoplacental unit. Altogether, our observations imply a restricted basal immune milieu in males compared to females, which may help understand the higher male susceptibility to adverse perinatal outcomes.