3.2 JAK/STAT expression pattern in lung
The expression of JAK/STAT in lung is mostly studied in the lung tumor (non-small-cell lung carcinoma), interstitial lung disease (ILD), asthma and acute lung injury. Different kinds of pulmonary diseases vary in the expression and distribution of JAK/STAT. Among the members of JAK and STAT protein families, JAK1, JAK2, and STAT1, STAT3 are most studied. Especially, JAK1/3 signaling pathways are considered key initiators of TH2 differentiation and lung allergic responses(Ashino et al., 2014). It is generally considered the JAK/STAT signaling is a transducer of cytokines, and many researches of JAK/STAT are about their role in immune cells, however, there is rarely study about their mechanism in pulmonary parenchyma cells.
JAK1/STAT3 signaling participated in the inflammation lung diseases. The activation of JAK1/STAT3 is related to many kinds of inflammation lung injury and is the cause or consequence of the imbalance in lung microenvironment. JAK1-associated PI3K signaling regulates gene induction of inflammation cytokines53. In addition, IL-17A is revealed of participating in the acute lung injury process, it upregulated p-JAK1/2, p-STAT1/3, stimulated inflammation gene induction in human airway epithelial cells by JAK1-associated PI3K signaling(Shaikh, Bhat & Bhandary, 2020). In the respiratory inflammatory response process, JAK1 and STAT3 stimulated the -500 to +41 promoter activity of the surfactant protein B (SP-B) gene in respiratory epithelial cells, influence on surfactant protein homeostasis(Yan, Naltner, Martin, Naltner, Fangman & Gurel, 2002).
Numerous studies show JAK1 is activated by many factors in the process of “one hit lung injury” (induced by virus infection, hyperoxia, tobacco, etc.) and “second hit lung injury” (such as ventilator induced lung injury), and inhibition of JAK1 is postulated to be able to reduce lung injury. In BEAS-2B cell, the viral infection process elevated JAK1 expression(Zhou, Wang, Li, Wang & Hou, 2021). In fetal type II epithelial cells, the mechanical stretch exposure activated IL-6-STAT3-SOCS3 signaling pathway decreased IL-10 signaling pathway, activated JAK1, TYK2 and finally induced the injury of mechanical(Hokenson, Wang, Hawwa, Huang, Sharma & Sanchez-Esteban, 2013). There are also studies about hyperoxia which found hyperoxia exposure activated IL-10 signaling and JAK1, TYK2(Lee & Lee, 2015). In primary human small airway epithelial cells, IL-13-induced metaplasia (expression of Muc5AC, Muc5B, and SPDEF) and it is due to the phosphorylation of JAK-1, ERK1/2, and STAT-6. The aldose reductase could prevent metaplasia of airway epithelial cells by inhibition of JAK/STAT(Yadav, Leopoldo, Ramana, Istvan, Srivastava & Melanie, 2010). In tobacco injured lung injury, inhibition of JAK1 and STAT3 decreased the SOCS-3 expression, and restored tobacco injured airway epithelial cells(Nasreen, Gonzalves, Peruvemba & Mohammed, 2014). In cultured human bronchial smooth muscle cells STAT6 phosphorylation/activation induced by IL-13 was mediated by activation of JAK1(Yoshihiko, Kumiko & Miwa, 2012).
Recent researches reveal that JAK3 abnormally activated in many lung diseases. JAK3 kinase is first cloned from rat tissues including spleen, lung, kidney, and intestine(Takahashi & Shirasaw, 1994). Subsequently, JAK3 is verified playing a vital role in the proliferation of hematopoietic cells especially T lymphocytes(Cetkovic-Cvrlje & Uckun, 2004) but then it was also found that JAK3 was important in myeloid cells and epithelial cell barrier function. Inflammation microenvironment abnormally activated JAK3 kinase, subsequently injured the epithelial barrier function, in return aggravated inflammation injury to epithelial cells. Cancer gene profile of lung cancer patients showed that there were JAK2 and JAK3 active mutations in the condition of lung diseases(Li et al., 2017). JAK3 inhibitors decreased MUC4 mRNA level of pseudo stratified columnar epithelium, alleviated epithelial cell injury, and regulated its hyperplasia(Damera, Xia & Sach De V, 2006). JAK3 transduce is also critical for eosinophil recruitment in airway inflammation(Li et al., 1999). The activating of JAK3/STAT5 pathway promotes airway smooth muscle cell inflammation(Zhu, Huang, Zhu & Cai). In the monocyte/macrophage, JAK3 signaling enhances IL-10 production leading to down-regulation of IL-1 beta-converting enzyme (ICE) activation and suppression of IL-1 beta processing and releasing. Hence, targeting JAK3 is potentially therapeutic to pulmonary inflammation and other lung diseases (idiopathic pulmonary fibrosis, COPD)(Li, Wang, Wang & Zhang, 2017; Yz et al.; Zhou, Zhuo & Cai, 2018).
Existing evidence suggests that JAK2 plays a negative role in pulmonary inflammation. Inhibition of JAK2, JAK1, STAT1, STAT3 and TYK2 ameliorate the acute lung injury or inflammation pathology(Li, Cao, Xiang, Hong & Huang, 2020; Liu, Dong, Bo, Li & Li, 2015; Song et al., 2015). There are also study shows that increasing of the tyrosine phosphorylation of TYK2, JAK3 induced STAT3 and STAT5 tyrosine phosphorylation, then stimulated proliferation of pulmonary epithelial cells(Liu & Kern, 2002).
Moreover, the JAK1/JAK2/STAT1/STAT3/STAT6 and TYK2 are also reported to have a closely connection with other pulmonary diseases like intestinal pulmonary fibrosis (IPF), pulmonary sarcoidosis(Montero, Milara, Roger & Cortijo, 2021). And up-regulation of their phosphorylated form is often related to disease progression and poor prognosis. These findings highlight that JAK-STAT signaling is closely linked with pulmonary physiology and pathophysiology.