Advancement in TPL2-regulated innate immune response

Tumor progression locus 2 (TPL2) in tumor-promoting Inflammation, Tumorigenesis and Tumor Immunity

“…TPL2-regulated genes include cytokines (TNF, IL-1α/β, IL-6, IL-17A, IFNγ and IL-10), chemokines (such as IL-8, CXC-chemokine ligand 1 (CXCL1), CC-chemokine ligand 3 (CCL3/MIP1α), CCL2/MCP1 and CCL5/RANTES), growth factors (granulocyte-macrophage colony-stimulating factor (GM-CSF) and vascular endothelial growth factor (VEGF)), proliferative proteins (peptidyl-prolyl cis/trans isomerase (Pin1), cyclooxygenase 2 (COX2) and cyclin D1) and matrix metalloproteinase (MMP2, MMP3, MMP9 and MMP13) 1 , 6 , 10 . TPL2 kinase is also implicated in the post-transcriptional regulation of TNFα, IL-6, COX2, IL-1β and IL-18 through multiple mechanisms, including nucleoplasmic transportation, mRNA stabilization, translation and protein secretion 5 , 16 - 18 .…”

“…The TPL2-regulated cytokines and chemokines further promote the recruitment of inflammatory cells such as macrophages, neutrophils and lymphocytes, which contribute to the inflammatory microenvironment 1 , 10 . These cells produce a plethora of inflammatory factors such as TNFα, IL-6, CXCL12 and CXCL1 that facilitate cell proliferation, cell survival, angiogenesis and metastasis through the activation of inflammatory and oncogenic pathways 6 , 10 .…”

“…The TPL2-regulated cytokines and chemokines further promote the recruitment of inflammatory cells such as macrophages, neutrophils and lymphocytes, which contribute to the inflammatory microenvironment 1 , 10 . These cells produce a plethora of inflammatory factors such as TNFα, IL-6, CXCL12 and CXCL1 that facilitate cell proliferation, cell survival, angiogenesis and metastasis through the activation of inflammatory and oncogenic pathways 6 , 10 . Some of the oncogenic pathways regulated by TPL2 include mitogen-activated protein kinase (MAPK), nuclear factor-kappa light-chain enhancer of activated B cells (NF-κB), activator protein 1 (AP-1), signal transducer and activator of transcription 3 (STAT3), mechanistic target of rapamycin (mTOR) and CCAAT/enhancer-binding protein β (C/EBPβ) (Table 1 ) 6 , 10 .…”

“…These cells produce a plethora of inflammatory factors such as TNFα, IL-6, CXCL12 and CXCL1 that facilitate cell proliferation, cell survival, angiogenesis and metastasis through the activation of inflammatory and oncogenic pathways 6 , 10 . Some of the oncogenic pathways regulated by TPL2 include mitogen-activated protein kinase (MAPK), nuclear factor-kappa light-chain enhancer of activated B cells (NF-κB), activator protein 1 (AP-1), signal transducer and activator of transcription 3 (STAT3), mechanistic target of rapamycin (mTOR) and CCAAT/enhancer-binding protein β (C/EBPβ) (Table 1 ) 6 , 10 . Hence, TPL2-mediated inflammatory signaling creates a positive feedback loop that demonstrates a plausible mechanism in which cancer cells and other cells manipulate the tumor microenvironment to promote pro-tumorigenic inflammation 19 .…”

“…Although there is extensive documentation of TPL2 role in inflammation, cancer and immune diseases, the importance of TPL2-driven inflammation in tumorigenesis and tumor immunity, as well as the underlying mechanisms that drive these processes, are not fully appreciated and understood 1 , 5 , 6 , 9 , 10 . Here, we attempt to dissect the molecular mechanisms in which TPL2 connects inflammation to tumorigenesis as well as tumor immunity by focusing on recent insight on the TPL2 function.…”