SUBSTANCE P REGULATES INFLAMMATORY PATHWAYS IN LYMPHATIC MUSCLE

Abstract

Substance P (SP), a neuropeptide that acts through the neurokinin receptors is associated with the sensory innervation of lymphoid tissue and modulates lymphatic contractile function and lymph flow. SP signaling is associated with several inflammatory pathologies. The role of lymphatics in body fluid homeostasis, lipid absorption and inflammation and immunity rely on the contractility of the lymphatic muscle cells (LMCs). We have shown that lymphatic contractile dysfunction is associated with perturbations in inflammatory mechanisms and that SP activates both inflammatory and contractile pathways in lymphatics. However, the specific inflammatory pathways and the resultant cytokines activated by SP in LMCs is unknown. We hypothesized that SP stimulates the pro‐survival AKT and MAPK pathways, and increases pro‐inflammatory cytokines. Cultured rat mesenteric LMCs were treated with SP (1 mM) and total RNA and protein were isolated at different time points (6 hr and 24 hr). Western analysis was carried out to detect the total and phosphorylated forms of AKT, JNK, GSK3b, b‐catenin, FOXO1 and PDCD4. b‐actin was used as control. The relative levels of inflammatory cytokines and chemokines, and specific inflammatory microRNAs (miRNAs) were analyzed by real time PCR. Our results indicate that SP activates the AKT and JNK pathways to significantly increase inflammatory cytokine and chemokine expression, and induces expression of miR 17–5p, miR19b and miR186 in the LMCs. Additionally, SP stimulates expression of genes, involved in lymphatic remodeling. Taken together our data demonstrate that SP activates multiple inflammatory signaling pathways in the LMCs that contribute to an inflammatory response in lymphatics during pathological conditions.Support or Funding InformationAmerican Heart AssociationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.