The Effect of Simvastatin on Infection-Induced Inflammatory Response of Human Fetal Membranes

Abstract

Problem: Inflammatory cytokines and matrix metalloproteinases (MMPs) contribute to preterm labor pathophysiology. The objective of this study was to test anti-inflammatory properties of simvastatin in human fetal membranes exposed to lipopolysaccharide (LPS).

Method of study: Normal term human fetal membrane explants (n = 11) were allocated to one of the six study groups: control, LPS only (100 ng/mL), simvastatin only (125 ng/mL), simvastatin given 6 hrs prior to LPS (S-L), simvastatin given 6 hrs post-LPS (L-S), and simvastatin and LPS given simultaneously (L+S). Explants were incubated for 24 hrs. Multiplex ELISA for cytokines: IL-1β, IL-6, IL-10, and TNF-α; soluble cytokine receptors: sIL-1R2, sIL-6R, sTNFR1, and R2; MMPs (1, 2, 7, 9, and 10); and tissue inhibitor of metalloproteinase-2 (TIMP-2) was performed on tissue culture supernatants. Pairwise comparison between different groups was conducted by least square mean estimates.

Results: Compared with controls, LPS stimulation increased cytokine production and their tissue bioavailability (measured as the molar ratio of cytokine to its soluble receptor), thus confirming membrane immune reactivity (P < 0.01). Pre-treatment with simvastatin (S-L) reduced IL-6 (P = 0.02), TNF-α (P = 0.02), and MMP-9 (P = 0.01); post-treatment (L-S) reduced IL-1β (P = 0.02) and TNF-α (P = 0.04), while simultaneous treatment (L+S) did not reduce any of the cytokines tested. Simvastatin reduced the molar ratio of TNF-α/sTNFR1 or R2 and IL-1β/sIL-1R2 (P = 0.01 and 0.04 in S-L group; P = 0.01 and 0.004 in L-S group, respectively). S-L additionally reduced MMP-9/TIMP-2 molar ratio (P = 0.0007).

Conclusions: Simvastatin downregulates LPS-induced inflammatory response and restores homeostasis between pro- and anti-inflammatory processes. Simvastatin may reduce fetal inflammatory response associated with infection-induced preterm birth.

Keywords: Cytokines; matrix metalloproteinases; pregnancy; preterm birth; preterm labor.