Salmonella fimbrial protein StcD induces cyclooxygenase-2 expression via Toll-like receptor 4

Introduction: The genome of Salmonella enterica serovar Typhimurium contains 13 operons with homology to fimbrial genes. Methods: To investigate the involvement of these fimbrial gene clusters in the expression of cyclooxygenase-2 (COX-2), which is an inducible enzyme involved in the synthesis of prostanoids, in J774 macrophages infected with S. enterica serovar Typhimurium, we constructed strains car-rying a mutation in genes encoding the putative subunit proteins in 12 fimbrial operons.Results: The level of COX-2 expression was lower in macrophages infected with fimA or stcA mutant Salmonella than in those infected with wild-type Salmonella. Therefore, we focused on putative subunit protein StcA and adhesive like protein StcD encoded in the stc operon. Treat-ment of macrophages with purified recombinant StcD protein, but not StcA, resulted in the acti-vation of the mitogen-activated protein kinase and nuclear factor kappa B signaling pathways, leading to the expression of not only COX-2 but also of pro-inflammatory cytokines such as inter-leukin (IL)-1b, IL-6, and tumor necrosis factor alpha. The expression of StcD-induced COX-2 was inhibited by treatment with the Toll-like receptor 4 (TLR4) inhibitor TAK-242, but not by treat-ment with the lipopolysaccharide (LPS) antagonist polymyxin B. Furthermore, StcD treatment stimulated HEK293 cells expressing TLR4 in the presence of CD14 and MD-2.Conclusion: StcD is a pathogen-associated molecular pattern of S. enterica serovar Typhimurium that is recognized by TLR4 and plays a significant role in the induction of COX-2 expression in macrophages.Copyright (c) 2021, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

This study revealed the relationship between fimbrial gene clusters in Salmonella enterica serovar Typhimurium and COX-2 expression, and identified StcD as a pathogen-associated molecular pattern recognized by TLR4 that plays a significant role in the induction of COX-2 in macrophages.