BackgroundGastric adenocarcinoma is the third most common cause of cancer-associated death worldwide. Helicobacter pylori infection activates a signaling cascade that induces production of cytokines and chemokines involved in the chronic inflammatory response that drives carcinogenesis. We evaluated circulating cytokines and chemokines as potential diagnostic biomarkers for gastric cancer.MethodsWe included 201 healthy controls and 162 patients with distal gastric cancer who underwent primary surgical resection between 2009 and 2012 in Mexico City. The clinical and pathological data of patients were recorded by questionnaire, and the cancer subtype was classified as intestinal or diffuse. Pathological staging of cancer was based on the tumor–node–metastasis staging system of the International Union Against Cancer. Concentrations of IL-1β, IL-6, TNF-α, IL-10, and MCP-1 in serum were measured using multiplex analyte profiling technology and concentrations of IL-8, IFN-γ, and TGF-β in plasma were measured using enzyme-linked immunosorbent assay.ResultsLevels of IL-1β, IL-6, IFN-γ, and IL-10 were significantly higher and that of MCP-1 was lower in gastric cancer patients compared with controls. No differences in IL-8 or TNF-α levels were observed between gastric cancer and controls. IFN-γ and IL-10 were significantly higher in both intestinal and diffuse gastric cancer, whereas IL-1β and IL-6 were higher and TGF-β lower only in intestinal gastric cancer; MCP-1 was lower only in diffuse gastric cancer. IFN-γ and IL-10 levels were significantly higher in early (I/II) and late stage (III/IV) gastric cancer; IL-1β and IL-8 were higher and MCP-1 was lower only in late stage (IV) patients. Receiver-operating characteristic analysis showed that for diagnosis of GC, IL-6 had high specificity (0.97) and low sensitivity (0.39), IL-10 had moderate specificity (0.82) and low sensitivity (0.48), and IL-1β and IFN-γ showed low specificity (0.43 and 0.53, respectively) and moderate sensitivity (0.76 and 0.71, respectively).ConclusionsIncreased levels of IL-6, IFN-γ, and IL-10 might be useful as diagnostic biomarkers for GC; however, this needs to be confirmed with larger number of patients and with control groups other than blood donors, properly age paired. IL-1β, IL-6, MCP-1, and TGF-β differentiate intestinal from diffuse GC. IFN-γ and IL-10 might be useful for diagnosis of early stage GC, and IL-1β, IL-8, and MCP-1 for late stages of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3310-9) contains supplementary material, which is available to authorized users.
TLRs and NLRs participate in the immune system recognition of Helicobacter pylori. However, little is known about the mechanisms leading to inflammasome activation by H. pylori and if NLRs in neutrophils are involved in the process. We studied how NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome components are involved in IL-1β maturation in human neutrophils in response to the infection and if they are dependent on T4SS (type IV secretion system) and TLRs. Human neutrophils were cultured and infected with the 26695 or the VirD4- H. pylori strains; the IL-1β concentration was analyzed by ELISA, and we also evaluated the activation of TLRs 2 and 4. The infection of neutrophils with both strains of H. pylori induced production of IL-1β and expression of the NLRP3 inflammasome components such as apoptosis-associated speck-like protein with CARD domain and NLRP3 protein. The infection also increased the activity of caspase-1, which is required for the maturation of IL-1β. Our study shows, for the first time, that H. pylori infection induces the expression and activation of components of NLRP3 inflammasomes in human neutrophils and that the activation is independent of a functional T4SS and TLR2 and TLR4.
Colonization of the gastric mucosa by Helicobacter pylori can lead to peptic ulcer and gastric adenocarcinoma. TLRs are signaling receptors involved in the recognition of microorganisms, and polymorphisms in their genes may influence the innate and adaptive immune response to H. pylori, affecting the clinical outcomes of the infection. We assessed the association between single nucleotide polymorphisms in TLR9 and TLR5 and gastroduodenal diseases. All patients were genotyped by allelic discrimination in regions 1174C>T and 1775A>G of TLR5 and -1237T>C and 2848G>A of TLR9. The 2848A allele of TLR9 was more frequent in duodenal ulcer and showed an association of risk with this pathology. Polymorphisms in TLR5 were not found to be associated with disease. Patients with polymorphisms in TLR9 and TLR5 expressed significantly lower levels of IL-1β and TNF-α, whereas polymorphisms in TLR5 also decreased the expression of IL-6 and IL-10. Our findings suggest that 2848G>A polymorphism in TLR9 increases the risk for the development of duodenal ulcer probably by modifying the inflammatory response to H. pylori infection. This is the first study to show an association of 2848A allele of TLR9 with duodenal ulcer and with altered expression of inflammatory cytokines in the gastric mucosa.
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