The JAK2 pathway is activated in idiopathic pulmonary fibrosis

Abstract

BackgroundIdiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal fibrotic disorder, with no curative therapies. The signal transducer and activator of transcription 3 (STAT3) protein is activated in lung fibroblasts and alveolar type II cells (ATII), thereby contributing to lung fibrosis in IPF. Although activation of Janus kinase 2 (JAK2) has been implicated in proliferative disorders, its role in IPF is unknown. The aim of this study was to analyze JAK2 activation in IPF, and to determine whether JAK2/STAT3 inhibition is a potential therapeutic strategy for this disease.Methods and resultsJAK2/p-JAK2 and STAT3/pSTAT3 expression was evaluated using quantitative real time-PCR, western blotting, and immunohistochemistry. Compared to human healthy lung tissue (n = 10) both proteins were upregulated in the lung tissue of IPF patients (n = 12). Stimulating primary ATII and lung fibroblasts with transforming growth factor beta 1 or interleukin (IL)-6/IL-13 activated JAK2 and STAT3, inducing epithelial to mesenchymal and fibroblast to myofibroblast transitions. Dual p-JAK2/p-STAT3 inhibition with JSI-124 or silencing of JAK2 and STAT3 genes suppressed ATII and the fibroblast to myofibroblast transition, with greater effects than the sum of those obtained using JAK2 or STAT3 inhibitors individually. Dual rather than single inhibition was also more effective for inhibiting fibroblast migration, preventing increases in fibroblast senescence and Bcl-2 expression, and ameliorating impaired autophagy. In rats administered JSI-124, a dual inhibitor of p-JAK2/p-STAT3, at a dose of 1 mg/kg/day, bleomycin-induced lung fibrosis was reduced and collagen deposition in the lung was inhibited, as were JAK2 and STAT3 activation and several markers of fibrosis, autophagy, senescence, and anti-apoptosis.ConclusionsJAK2 and STAT3 are activated in IPF, and their dual inhibition may be an attractive strategy for treating this disease.Electronic supplementary materialThe online version of this article (10.1186/s12931-018-0728-9) contains supplementary material, which is available to authorized users.

TGF-β pathway activation by idiopathic pulmonary fibrosis (IPF) fibroblast derived soluble factors is mediated by IL-6 trans-signaling

“…This reduction in SOCS3 was previously shown in other fibrotic conditions [33,40]. Nevertheless, a recent study by Milara et al showed that lungs from patients with IPF expressed higher levels of STAT3 and JAK2, as well as phosphorylated STAT3 [32]. In another article they showed that this was also the case in pulmonary arteries in IPF [29].…”

“…A recent study by Milara et al showed that IL-6, via STAT3 phosphorylation, induced proliferation and migration of primary human fibroblasts. They also showed that IL-6 is elevated in BAL and in lung tissues of rats following bleomycin treatment [32].…”

Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 to Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution

“…Persistently activated STAT3, independently as well as in conjunction with TGF-b, drives unregulated wound healing, leading to fibrosis through overexpression of ECM components, e.g., COL1A2 (Papaioannou et al, 2018), MMPs (Matsui et al, 2017), and promoting apoptosis resistance of fibroblasts (Moodley et al, 2003;Habiel and Hogaboam, 2014;Xu et al, 2014a;Milara et al, 2018), aberrant EMT (Kasembeli et al, 2018), etc.…”

Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment

“…In rats administered JSI-124, a Jak2 inhibitor that targets STAT3 indirectly, several markers of bleomycin-induced lung fibrosis were reduced [52]. Several other Jak inhibitors, e.g., Cucurbitacin B, Pacritinib and Ruxolitinib, are at various stages of preclinical and clinical development (Table 1).…”