Abstract
BackgroundInterleukin-33 (IL-33) is an effective inducer of pro-inflammatory cytokines regulating innate and adaptive immunity. Inflammation could be a double-edged sword, promoting or inhibiting tumour growth. To date, the roles and mechanisms of IL-33 in tumours remain controversial. Here, we examined the effect of exogenous IL-33 on the biological characteristics of hepatocellular carcinoma (HCC) and the possible mechanism of action.MethodsIn this study, IL-33 expression in the tissues of 69 HCC patients was detected and its relationship with prognosis was evaluated. After establishing a mouse HCC model and IL-33 treatment operation, the infiltration of splenic myeloid-derived suppressor (MDSCs), dendritic (DCs), regulatory T, and natural killer (NK) cells was detected by flow cytometry analysis, and the vascular density of the tumour tissues was detected by immunohistochemistry to reveal the mechanism of IL-33 in HCC proliferation. Finally, the Cancer Genome Atlas database was used to analyse Gene Ontology terms the and Kyoto Encyclopaedia of Genes and Genomes pathway. Moreover, the chi-square test, two-tailed unpaired Student’s t-test, and multiple t-tests were performed using SPSS version 23.0 and GraphPad Prism 8.0 software.ResultsThe IL-33 expression level was negatively correlated with the overall survival of HCC patients, suggesting its potential clinical significance in the prognosis of HCC. We found that systemic IL-33 administration significantly promoted the tumour size in vivo. Furthermore, the IL-33-treated mice presented decreased frequencies of tumouricidal NK and CD69+ CD8+ T cells. After IL-33 treatment, the incidence of monocytic MDSCs and conventional DCs increased, while that of granulocytic MDSCs decreased. Moreover, IL-33 promoted the formation of intracellular neovascularization. Therefore, IL-33 accelerated HCC progression by increasing the accumulation of immunosuppressive cells and neovascularization formation. Finally, we found that the transcription of IL-33 was closely related to the PI3K-Akt and MAPK pathways in Gene Set Enrichment Analysis plots, which were involved in the tumourigenesis and pathogenesis of HCC.ConclusionsTaken together, IL-33 may be a key tumour promoter of HCC proliferation and tumourigenicity, an important mediator, and a potential therapeutic target for regulating HCC progression.
Highlights
Interleukin-33 (IL-33) is an effective inducer of pro-inflammatory cytokines regulating innate and adaptive immunity
IL‐33 is upregulated in hepatocellular carcinoma (HCC) To determine the role of IL-33 in HCC patients, we initially explored IL-33 expression in a tissue array containing 69 HCC and 64 paired adjacent normal tissue samples
High IL‐33 expression in HCC correlates with poor patient survival and advanced clinicopathological features To understand the clinical implications of upregulating IL-33, we analysed the correlation between IL-33 expression and clinicopathological characteristics in HCC patients
Summary
Interleukin-33 (IL-33) is an effective inducer of pro-inflammatory cytokines regulating innate and adaptive immunity. The roles and mechanisms of IL-33 in tumours remain controversial. Interleukin-33 (IL-33) has been described as a potent promoter of type II immunity that triggers an innate immune response to allergic inflammation and parasitic infections [1]. Wang et al J Transl Med (2020) 18:477 found to be involved in the occurrence of many diseases, such as atherosclerosis [2] and obesity [3], and plays a pro-inflammatory role in asthma [4] and antigen-induced arthritis [5]. IL-33 recruits signal adapters and kinases to activate transcription factors in tumour cells, which produce the tumourassociated inflammatory microenvironment [7]
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