Inflammasomes play important roles in the pathogenesis of tumors, but the roles of NLRP3 inflammasome in the lymphoma remain unclear. Activated NLRP3 inflammasome induces the maturation of its effector cytokine IL-18 which functions in the development of cancer. Here, we investigated the polymorphism and expression of NLRP3 inflammasome related genes and explored their function in lymphoma. We found that IL-18 (rs1946518) and NFκB94 ins/del (rs28362491) contributed to lymphoma susceptibility and allele G in IL-18 was significantly associated with the risk of lymphoma. The mRNA and plasma expression levels of IL-18 were significantly elevated in primary lymphoma patients and decreased after remission. NLRP3 inflammasome could be activated by ATP plus LPS in lymphoma cells accompanied with the increasing expression of NLRP3-related genes. NLRP3 inflammasome activation reduced the dexamethasone-induced proliferation-inhibiting effect by promoting cells into S phase. NLRP3 inflammasome activation promoted lymphoma cells proliferation and inhibited apoptosis through up-regulation of c-myc and bcl-2, and down-regulation of TP53 and bax, and then reduced the anti-tumor effect of dexamethasone. Similar with the activation of NLRP3, the effector cytokine IL-18 also had the proliferation-promoting, apoptosis-inhibiting and resistance-reducing effects on lymphoma cells via shifting the balance of c-myc/TP53 and bcl-2/bax. Moreover, neutralizing IL-18 has the opposite effects. In conclusion, NLRP3 inflammasome contributes to the susceptibility and plays a carcinogenic role through its effector cytokine IL-18 in lymphoma.

Acute myeloid leukemia (AML) harbors an immune suppression environment, featured by increased regulatory T cells (Tregs). The expression of tumor necrosis factor receptor-2 (TNFR2) on Tregs could be used to identify the maximally suppressive Treg population, and TNF-α furtherly promoted the expansion and function of Tregs via TNFR2 in mice. However, the role of TNF-α has not been determined in AML patients. In view of high levels of TNF-α and Tregs in AML patients, we hypothesized that the increased frequency of Tregs may rely on TNF-α–TNFR2 pathway. We investigated the levels of TNFR2+ Tregs and TNF-α secreted by T cells in peripheral blood (PB) of AML by flow cytometry and enzyme-linked immunosorbent assay, respectively. Our results showed the elevated plasma TNF-α in PB of newly diagnosed (ND) AML patients. The production of TNF-α by CD4+ T cells, especially by T helper (Th)17 cells was remarkably higher in ND AML patients than in complete remission (CR) patients and healthy controls. Then, we found that the circulating frequencies of CD4+CD25+ Tregs and CD4+CD25high Tregs in AML patients were elevated compared with those in healthy controls and CR patients. TNFR2 expression was much higher on Tregs in AML patients and was preferentially expressed on CD4+CD25high T cells. Furthermore, we confirmed that, in vitro, the additional TNF-α can increase the frequency of Tregs through TNFR2 in both AML patients and healthy controls. Summarily, in AML patients, the abnormally elevated level of TNF-α secreted by CD4+ T especially Th17 cells promoted the higher Tregs frequency via the TNF-α–TNFR2 pathway.

Acute myeloid leukemia (AML) is a hematological malignancy in which the immune response serves a pivotal role in progression. Aryl hydrocarbon receptor (AHR) is involved in the modulation of the immune system, particularly in the differentiation of T-helper cell (Th) subsets. Although the NLR family pyrin domain-containing 3 (NLRP3) inflammasome has been implicated as essential in the pathogenesis of autoimmune and inflammatory diseases, the role it serves in the development of AML remains unknown. Therefore, in order to identify and describe the possible roles of AHR, as well as NLRP3 inflammasome, in the pathogenesis of AML and their relationship with Th subsets (Th1 Th22), the present study investigated the mRNA expression levels of AHR and NLRP3 inflammasome molecules in the peripheral blood and bone marrow. Concentrations of plasma IL-18 were also investigated in peripheral blood by ELISA, as well as the proportions of Th22 and Th1. In the present study, there were three groups: Newly diagnosed (ND) patients; complete remission (CR); and normal controls. A markedly increased expression of NLRP3 inflammasome molecules in bone marrow mononuclear cells (BMMCs) from newly diagnosed (ND) patients compared with patients in complete remission (CR) was identified. NLRP3 inflammasome molecules were also observed to be aberrantly expressed in peripheral blood (PB) mononuclear cells (PBMCs), accompanied with aberrant interleukin (IL)-18 levels in PB plasma. The relative level of IL-18 mRNA became normal after the ND patients with AML achieved CR. In bone marrow, the expression of AHR was significantly higher in ND patients than in CR patients. Furthermore, the expression level of NLRP3 inflammasome molecules was significantly correlated with AHR expression in patients with AML. In the Th subsets, a significantly increased proportion of Th22 in PB from ND patients compared with CR patients or controls was identified, accompanied with decreased Th1. It was concluded that the NLRP3 inflammasome, associated with AHR, was involved in the development of AML and may have influenced the differentiation of Th subsets.

NLRP3 inflammasome has been reported to be associated with the pathogenesis of multiple solid tumors. However, the role of NLRP3 inflammasome in acute myeloid leukemia (AML) remains unclear. We showed that NLRP3 inflammasome is over-expressed and highly activated in AML bone marrow leukemia cells, which is correlated with poor prognosis. The activation of NLRP3 inflammasome in AML cells promotes leukemia cells proliferation, inhibits apoptosis and increases resistance to chemotherapy, while inactivation of NLRP3 by caspase-1 or NF-κB inhibitor shows leukemia-suppressing effects. Bayesian networks analysis and cell co-culture tests further suggest that NLRP3 inflammasome acts through IL-1β but not IL-18 in AML. Knocking down endogenous IL-1β or anti-IL-1β antibody inhibits leukemia cells whereas IL-1β cytokine enhances leukemia proliferation. In AML murine model, up-regulation of NLRP3 increases the leukemia burden in bone marrow, spleen and liver, and shortens the survival time; furthermore, knocking out NLRP3 inhibits leukemia progression. Collectively, all these evidences demonstrate that NLRP3 inflammasome promotes AML progression in an IL-1β dependent manner, and targeting NLRP3 inflammasome may provide a novel therapeutic option for AML.

IL-1β (rs16944) and IL-18 (rs1946518) may be served as potential predictors for AML.