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Receptor-interacting protein kinase 2 contributes to host innate immune responses against Fusobacterium nucleatum in macrophages and decidual stromal cells

Problem: Chorioamnionitis is caused by a bacterial infection that ascends from the vagina and can cause adverse pregnancy outcomes (APOs). Fusobacterium nucleatum (F. nucleatum) is a periodontal pathogen associated with the occurrence of APOs. In this study, we evaluated whether receptor-interacting protein kinase 2 (Ripk2), an adaptor protein of the cytosolic receptors NOD1 and NOD2, in macrophages and human decidual stromal cells (hDSCs) contributes to immune responses against F. nucleatum.

Method of study: Bone marrow-derived macrophages (BMDMs) isolated from wild-type (WT) and Ripk2-deficient mice and hDSCs were cultured with F. nucleatum (MOI 1, 10, 100). BMDMs and hDSCs were assessed using enzyme-linked Immunosorbent assay (ELISA), Western blot analysis, real time PCR, and nitrite assay.

Results: F. nucleatum-induced production of IL-6, but not of TNF-α and IL-10, was lower in Ripk2-deficient BMDMs than in WT cells. Western blotting revealed a decrease in F. nucleatum-induced p65 phosphorylation in Ripk2-deficient macrophages, whereas mitogen-activated protein kinases (MAPKs) activation was comparable between WT and Ripk2-deficient cells. The production of nitric oxide in response to F. nucleatum and the gene and protein expression of inducible nitric oxide synthase (iNOS) was impaired in Ripk2-deficient BMDMs. In hDSCs, F. nucleatum upregulated the gene and protein expression of NOD1, NOD2, and Ripk2 in a time-dependent manner. F. nucleatum also increased the production of IL-6, CXCL8, and CCL2, whereas this production was decreased by the Ripk2 inhibitors SB203580 and PP2.

Conclusions: In conclusion, Ripk2 signaling appears to contribute to the F. nucleatum-induced immune response and can be a preventive and therapeutic target against APOs.

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