Endogenous IL-33 and Its Autoamplification of IL-33/ST2 Pathway Play an Important Role in Asthma

Abstract

Cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD-1) are immune checkpoint proteins expressed in T cells. Although CTLA4 expression was found in multiple tumours including non-small cell lung cancer (NSCLC) tissues and cells, its function in tumour cells is unknown. Recently, PD-1 was found to be expressed in melanoma cells and to promote tumorigenesis. We found that CTLA4 was expressed in a subset of NSCLC cell lines and in a subgroup of cancer cells within the lung cancer tissues. We further found that in NSCLC cells, anti-CTLA4 antibody can induce PD-L1 expression, which is mediated by CTLA4 and the EGFR pathway involving phosphorylation of MEK and ERK. In CTLA4 knockout cells, EGFR knockout cells or in the presence of an EGFR tyrosine kinase inhibitor, anti-CTLA4 antibody was not able to induce PD-L1 expression in NSCLC cells. Moreover, anti-CTLA4 antibody promoted NSCLC cell proliferation in vitro and tumour growth in vivo in the absence of adaptive immunity. These results suggest that tumour cell-intrinsic CTLA4 can regulate PD-L1 expression and cell proliferation, and that anti-CTLA4 antibody, by binding to the tumour cell-intrinsic CTLA4, may result in the activation of the EGFR pathway in cancer cells.

Contributions of IL-33 in Non-hematopoietic Lung Cells to Obstructive Lung Disease

“…Indeed, IL-33 stimulation of human airway epithelial cells in vitro induces IL-33 mRNA upregulation, although ST2 expression is not affected (11,57). In mouse models, airway administration of IL-33 enhances both IL-33 and ST2 expression in lung epithelial cells (11,43,59). Moreover, IL-33 and IL-13 work synergistically to enhance IL-33 expression in bronchial epithelial cells (11).…”

Molecular Hydrogen Alleviates Asthma Through Inhibiting IL-33/ILC2 Axis

“…Hydrogen gas did not change IL-33 promoter activity, and mRNA and protein levels in 16HBE cells alone but signi cantly suppressed HDM induced overexpression of IL-33, indicating molecular hydrogen not only acted as an antioxidant [17,20] but also modulated IL-33 expression through regulating its transcription in HDM activated 16HBE cells. Meanwhile, IL-33 receptor ST2 exhibited a similar pattern as IL-33 in response to HDM and hydrogen treatments, meaning that molecular hydrogen blocked the autoampli cation of IL-33/ST2 pathway [28].…”

“…Hydrogen gas reduced serum and BALF IL-33, IL-4, IL-25, and TSLP levels as well as lineage − ICOS + ST2 + ILC2 population of asthmatic mice. The population of ILC2 was positively correlated with IL-33 level, indicating molecular hydrogen was capable of mitigating OVA induced type II in ammation through targeting IL-33/ST2 pathway [28].…”

“…MicroRNA-21 was found to drive severe, steroidinsensitive allergic airway disease through targeting phosphatase and tensin homolog (PTEN) to regulate PI3K pathway [36]. IL-33 has been shown as the major player for activation of ILC2s [8,[26][27][28], the increased level of IL-33 was found in both serum and bronchoalveolar lavage uid in OVA induced asthmatic mice would activate lung ILC2 population. Lineage − ICOS + ST2 + ILC2 population was signi cantly increased in OVA-induced asthmatic mice.…”

What Makes the Lung Unique – Tissue-Specific Immunity in the Respiratory Tract

“…While generally thought of as an alarmin and indicator of tissue damage, in the lung it is already highly expressed in the steady-state by lung epithelial cells and is critically important in the induction 33 and exacerbation of allergic immune responses, including the development of asthma. 52 Indeed, IL-33 single nucleotide polymorphisms are strongly associated with asthma in humans. 53 In this context, IL-33 appears to be of particular importance in early life 54 and involved in promoting virus-induced asthma exacerbations.…”