IL-6 Cooperates with G-CSF To Induce Protumor Function of Neutrophils in Bone Marrow by Enhancing STAT3 Activation

Abstract

Neutrophils are known to have antitumor potential. However, in recent years the tumor-promoting effect of neutrophils has been well demonstrated. So far, it remains unclear what causes the conversion of neutrophil function from tumor suppressive to tumor promoting. In this article, we report that the conversion of murine neutrophil function occurs in bone marrow, and that IL-6 cooperation with G-CSF is required for this conversion. IL-6 cooperated with G-CSF to modulate neutrophils in bone marrow, altering the activation potential of signaling pathways in neutrophils, especially that of STAT3. Costimulation with G-CSF and IL-6 induced a higher level of phospho-STAT3 in neutrophils, which was further increased by upregulation of STAT3 expression in neutrophils owing to downregulation of IFN-β expression in bone marrow macrophages by IL-6. Augmented STAT3 activation was crucial for upregulating the expression of Mmp9 and Bv8 genes and downregulating the expression of Trail and Rab27a genes in neutrophils. Moreover, G-CSF/IL-6–modulated neutrophils could not efficiently release azurophilic granules because of downregulation of Rab27a and inefficient activation of PI3K and p38 MAPK pathways. Because of premodulation by G-CSF and IL-6, neutrophils in response to complex stimuli in tumor released much less myeloperoxidase, neutrophil elastase, and TRAIL, but showed much higher expression of Mmp9 and Bv8 genes. Taken together, these results demonstrate that G-CSF and IL-6, despite their well-known physiological functions, could modulate the activation potential of signaling pathways in neutrophils, resulting in the production or release of the above-mentioned factors in a way that favors tumor angiogenesis and tumor growth.

G-CSF does not influence C2C12 myogenesis despite receptor expression in healthy and dystrophic skeletal muscle

“…The actions of G-CSF may therefore require the interaction with other cytokines and growth factors in vivo . For example G-CSF is known to cooperate with stem cell factor in haematopoiesis (Duarte and Franf, 2002) and IL-6 during bone marrow stem cell tumour progression (Yan et al, 2013). Alternatively, it may act directly on other cell populations, such as immune cells to stimulate the release of factors that are able to act directly on muscle cells.…”

G-CSF Promotes Neuroblastoma Tumorigenicity and Metastasis via STAT3-Dependent Cancer Stem Cell Activation

“…In breast and lung carcinoma models, exogenous or tumor-derived G-CSF promotes expansion of myeloid-derived suppressor cell (MDSC) subsets within the circulation and tumor microenvironment (19, 32). These MDSCs in turn secrete pro-angiogenic factors and down-regulate pro-apoptotic TRAIL and MPO leading to tumor progression and metastatic spread to the lung (33, 34). These results are consistent with our findings that G-CSF promotes overall tumorigenicity and metastasis.…”

BST-2/tetherin is overexpressed in mammary gland and tumor tissues in MMTV-induced mammary cancer

“…It is however interesting that we observed the presence of both IL6 and G-CSF in TCM because previous work by others have shown that IL6 and G-CSF are produced by tumor and/or stromal cells in malignant tumors (Shojaei et al, 2007). IL6 and G-CSF in conjunction with phospho-STAT3 have been implicated in the protumor function of neutrophils (Yan et al, 2013). Furthermore, G-CSF is involved in promoting tumor angiogenesis (Okazaki et al, 2006; Shojaei et al, 2009) and increased levels of serum IL-6 have been associated with poor prognosis in human mammary cancer (Zhang and Adachi, 1999).…”