Investigating the immune modulatory properties of kisspeptin: implications for pregnancy

Botha, Stefan Marc

Investigating the immune modulatory properties of kisspeptin: implications for pregnancy

Master Thesis

2020

Publisher

University of Cape Town

Department

Division of Medical Biochemistry

Faculty

Faculty of Health Sciences

Abstract

Pregnancy is dependent on the development of maternal immune tolerance to the genetically foreign fetus. During pregnancy the mother's immune reactivity and energy metabolism undergoes significant changes and the levels of certain hormones in peripheral blood are significantly increased. Hormones are important regulators of the functional activity of the immune system and immune cells within. Hormones secreted by the placenta, protect the fetus from the maternal immune response of the mother, emphasizing their immunomodulatory effects. Therefore, hormonal regulation is essential for the functional activity of immune cells. There is evidence that the hormone, kisspeptin, plays a role in the development of immune tolerance during pregnancy based on its role in the regulation of the adaptive T regulatory (aTreg)/T-helper 17 (Th17) cells, induction of the enzyme indoleamine 2,3-dioxygenase (IDO) and regulation of monocyte function during pregnancy. In addition, kisspeptin has been implicated in the regulation of specific cytokines during pregnancy. It is crucial to maintain an appropriate cytokine balance at the maternal– fetal interface as well as in circulation. Several pregnancy-related disorders have been associated with a variation in Th1/Th2/Th17 cytokines and aTreg cell subsets. Kisspeptin has been implicated in regulating cytokines IL-10 and IL-17A as well as aTreg and Th17 cells which are significant role players in immune tolerance during pregnancy. However, its effect on other pro- and anti-inflammatory cytokines remain unknown. Therefore, more research is required to better understand the role of kisspeptin in the development of immune tolerance during pregnancy. The hypothesis of this study is that kisspeptin alters the expression of anti-and pro-inflammatory cytokines and may thus influence the establishment of immune tolerance in pregnancy. To test this hypothesis, we used a previously established in vitro peripheral blood mononuclear cell (PBMC) Mycobacterium tuberculosis (Mtb) infection assay model as well as a newly established in vitro infection model using lipopolysaccharide (LPS)-stimulated whole blood. Protein expression analysis of selected pro- and anti-inflammatory cytokines was performed on PBMC infected with Mtb and on whole blood cells stimulated with LPS in the absence and presence of kisspeptin-10 for different times. The cytokines levels were measured by luminex multiplex assay and sandwich ELISA, respectively. Results from the PBMC infection assay showed a varied but not statistically significant effect of kisspeptin-10 on selected pro- and anti-inflammatory cytokine expression at 2 hours post-infection. However, there was a suggestion of an inhibitory effect of kisspeptin-10 on selected pro- and anti-inflammatory cytokine expression, macrophage inflammatory protein (MIP)-1α, MIP-1β, tumour necrosis factor (TNF)-α, granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin (IL)-10, after 24 hours which was not observed at 6 days post-infection. Results from the whole blood stimulation assay suggested an inhibitory effect of kisspeptin-10 on selected LPS-induced pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) whilst generally not having an effect on selected anti-inflammatory cytokines (IL-10). Overall this study suggests, based on the lack of statistically significant data, a potential immunomodulatory effect of kisspeptin-10 based on the observed inhibition of pro-inflammatory cytokines. Investigating and developing an understanding of key regulators and mechanisms of maternal immune tolerance may help researchers understand the pathophysiological mechanisms underlying certain pregnancy-related disorders. This was a pilot study aimed at characterising the effect of kisspeptin stimulation on cytokines and chemokines responses. Manipulation of regulatory hormones such as kisspeptin could represent a potentially novel approach in the treatment of various pregnancy-related disorders including preeclampsia and unexplained recurrent miscarriage.

Keywords

Medical Biochemistry

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