Saturated fatty acids enhance TLR4 immune pathways in human trophoblasts

• Published in: Human reproduction (Oxford) 2015-09, Vol.30 (9), p.2152-2159
• Main Authors: Yang, Xiaohua, Haghiac, Maricela, Glazebrook, Patricia, Minium, Judi, Catalano, Patrick M., Hauguel-de Mouzon, Sylvie
• Format: Article
• Language: English
• Subjects: Adult; Cytokines - metabolism; Fatty Acids - metabolism; Female; Humans; Inflammation - metabolism; Interleukin-6 - metabolism; Interleukin-8 - metabolism; NF-kappa B - metabolism; Original; Pregnancy; Signal Transduction - physiology; Toll-Like Receptor 4 - metabolism; Trophoblasts - immunology; Trophoblasts - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0268-1161; 1460-2350
• DOI: 10.1093/humrep/dev173

STUDY QUESTION What are the effects of fatty acids on placental inflammatory cytokine with respect to toll-like receptor-4/nuclear factor-kappa B (TLR4/NF-kB)? SUMMARY ANSWER Exogenous fatty acids induce a pro-inflammatory cytokine response in human placental cells in vitro via activation of TLR4 signaling pathways. WHAT IS KNOWN ALREADY The placenta is exposed to changes in circulating maternal fatty acid concentrations throughout pregnancy. Fatty acids are master regulators of innate immune pathways through recruitment of toll-like receptors and activation of cytokine synthesis. STUDY DESIGN, SIZE, DURATION Trophoblast cells isolated from 14 normal term human placentas were incubated with long chain fatty acids (FA) of different carbon length and degree of saturation. The expression and secretion of interleukin-6 (IL-6), IL-8 and tumor necrosis factor-alpha (TNF-α) were measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Antibodies against TLR4 ligand binding domain, downstream signaling and anti-p65 NFkB-inhibitor were used to characterize the pathways of FA action. PARTICIPANTS/MATERIALS, SETTING, METHODS General approach used primary human term trophoblast cell culture. Methods and end-points used real-time quantitative PCR, cytokine measurements, immunohistochemistry, western blots. MAIN RESULTS AND THE ROLE OF CHANCE The long chain saturated fatty acids, stearic and palmitic (PA), stimulated the synthesis as well as the release of TNF-α, IL-6 and IL-8 by trophoblast cells (2- to 6-fold, P < 0.001). In contrast, the unsaturated (palmitoleic, oleic, linoleic) acids did not modify cytokine expression significantly. Palmitate-induced inflammatory effects were mediated via TLR4 activation, NF-kB phosphorylation and nuclear translocation. LIMITATIONS, REASONS FOR CAUTION TNF-α protein level was close to the limit of detection in the culture medium even when cells were cultured with PA. WIDER IMPLICATIONS OF THE FINDINGS These mechanisms open the way to a better understanding of how changes in maternal lipid homeostasis may regulate placental inflammatory status. STUDY FUNDING/COMPETING INTEREST(S) X.Y. was recipient of fellowship award from West China Second University Hospital, Sichuan University (NIH HD 22965-19). The authors have nothing else to disclose. TRIAL REGISTRATION NUMBER None.