Positive feedback regulation between IL10 and EGFR promotes lung cancer formation

Abstract

The role of IL10 in the tumorigenesis of various cancer types is still controversial. Here, we found that increased IL10 levels are correlated with a poor prognosis in lung cancer patients. Moreover, IL10 levels were significantly increased in the lungs and serum of EGFRL858R- and Kras4bG12D-induced lung cancer mice, indicating that IL10 might facilitate lung cancer tumorigenesis. IL10 knockout in EGFRL858R and Kras4bG12D mice inhibited the development of lung tumors and decreased the levels of infiltrating M2 macrophages and tumor-promoting Treg lymphocytes. We also showed that EGF increases IL10 expression by enhancing IL10 mRNA stability, and IL10 subsequently activates JAK1/STAT3, Src, PI3K/Akt, and Erk signaling pathways. Interestingly, the IL10-induced recruitment of phosphorylated Src was critical for inducing EGFR through the activation of the JAK1/STAT3 pathway, suggesting that Src and JAK1 positively regulate each other to enhance STAT3 activity. Doxycycline-induced EGFRL858R mice treated with gefitinib and anti-IL10 antibodies exhibited poor tumor formation. In conclusion, IL10 and EGFR regulate each other through positive feedback, which leads to lung cancer formation.

Inhaled IL-10 Suppresses Lung Tumorigenesis via Abrogation of Inflammatory Macrophage–Th17 Cell Axis

“…Whereas our data demonstrate a therapeutic role for IL-10 in the LSLKras model of lung tumorigenesis, others have found that IL-10-producing tumor cell lines can display enhanced growth in mice (36)(37)(38). This observation is likely associated with the early paracrine effects of IL-10 on the injected tumor cells and/or local angiogenic activity in the absence of a preexisting immune response.…”

Hepatitis C Virus E2 Envelope Glycoprotein Induces an Immunoregulatory Phenotype in Macrophages

“…This effect was observed by engagement of CD81 at a higher concentrations (10 or 30 μg/mL) of JS‐81 antibody alone, but was negligible at a lower CD81 engaging JS‐81 antibody concentration (<10 μg/mL). IL‐10 and EGFR regulate each other through positive feedback, and IL‐10 subsequently activates Stat3 signaling pathways. CBH‐2 mAb inhibits E2‐CD81 binding.…”

“…Inhibition of Akt is associated with a reduction in M2‐associated gene expression, indicating that activation of Akt is involved in macrophage polarization to the M2 phenotype. IL‐10 and EGFR regulate each other through positive feedback, and IL‐10 subsequently activates Stat3 signaling pathways. Furthermore, induction of IL‐10 in macrophages is associated with Akt activation .…”

‘Repair’ Treg Cells in Tissue Injury

“…Additionally, IL-10 signals that are required for EGFR induction has also been reported. Of note, IL-10-induced EGFR expression requires activation and recruitment of Src to IL-10 receptor subunit α, which increases JAK1/STAT3 signalling activity and results in the expression of EGFR [56]. …”