Abstract
IL-35 is an immunosuppressive cytokine and exerts regulatory effects on T cells, B cells, macrophages and dendritic cells. Neutrophils are important innate immune cells that play key roles in tumor development. The effect of IL-35 on neutrophils remains unknown. Here, we report that IL-35 can induce N2 neutrophil polarization (protumor phenotype) by increasing G-CSF and IL-6 production, and promote neutrophil infiltration into tumor microenvironment. The sustained expression of IL-35 could promote chronic inflammation to augment the proangiogenic and immunosuppressive function of neutrophils. IL-35 stimulated macrophages to secrete proinflammatory cytokines IL-1β and IL-6. IL-1β stimulated γδ T cells to produce IL-17, which in turn increased the production of G-CSF. By increasing the expression of G-CSF and IL-6, IL-35 could up-regulate the expression of MMP-9 and Bv8, and down-regulate TRAIL expression in neutrophils, thus augmenting the proangiogenic function of neutrophils. Moreover, G-CSF/IL-6 induced the enhanced activation of STAT3 and ERK pathways in neutrophils, thus increasing the expression of iNOS to suppress T cell activation. Our findings suggest that IL-35 can promote tumor progression by functioning as an up-stream cytokine to promote cancer-associated inflammation and control neutrophil polarization. Targeting IL-35 might be an important approach for designing new strategy of tumor therapy.
Highlights
Inflammation, especially chronic inflammation, is a driving force for tumor initiation and progression
To explore the effect of IL-35 on neutrophils in vivo, we fist investigated whether IL-35, as part of its effect on inflammation, may influence neutrophil infiltration in tumor microenvironment
We analyzed the amount of neutrophils in the tumor tissues after the inoculation of tumor cells to naive mice and the mice with in vivo transfection of IL-35 expression vector (IL35-mice)
Summary
Inflammation, especially chronic inflammation, is a driving force for tumor initiation and progression. Given that a chronic inflammatory microenvironment is an essential component of all of tumors [1], it is possible that IL-35 may promote tumor development by facilitating chronic inflammation. Neutrophils are the important components of inflammatory response, which have dual roles in tumor development and metastasis. Neutrophils are activated by chronic www.impactjournals.com/oncotarget inflammation to promote tumor growth and metastasis. The inflammatory cytokines such as G-CSF, IL-6 and TGF-β1 can induce N2 phenotype of neutrophils in bone marrow and tumor microenvironment [13, 14]. Our data showed that IL-35 could function as an up-stream cytokine to promote cancer-associated inflammation, and that IL-35 could induce the polarization of neutrophils towards N2 phenotype, facilitating tumor development
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