Abstract
Idiopathic pulmonary fibrosis (IPF) is one of the most symptomatic progressive fibrotic lung diseases, in which patients have an extremely poor prognosis. Therefore, understanding the precise molecular mechanisms underlying pulmonary fibrosis is necessary for the development of new therapeutic options. Stress-activated protein kinases (SAPKs), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38) are ubiquitously expressed in various types of cells and activated in response to cellular environmental stresses, including inflammatory and apoptotic stimuli. Type II alveolar epithelial cells, fibroblasts, and macrophages are known to participate in the progression of pulmonary fibrosis. SAPKs can control fibrogenesis by regulating the cellular processes and molecular functions in various types of lung cells (including cells of the epithelium, interstitial connective tissue, blood vessels, and hematopoietic and lymphoid tissue), all aspects of which remain to be elucidated. We recently reported that the stepwise elevation of intrinsic p38 signaling in the lungs is correlated with a worsening severity of bleomycin-induced fibrosis, indicating an importance of this pathway in the progression of pulmonary fibrosis. In addition, a transcriptome analysis of RNA-sequencing data from this unique model demonstrated that several lines of mechanisms are involved in the pathogenesis of pulmonary fibrosis, which provides a basis for further studies. Here, we review the accumulating evidence for the spatial and temporal roles of SAPKs in pulmonary fibrosis.
Highlights
The stress-activated protein kinase (SAPK) group of mitogen-activated protein kinases (MAPKs) are Ser/Thr kinases and include two members of the c-Jun NH2-terminal kinase (JNK) and p38 MAPK families, which are activated in response to environmental stresses such as UV irradiation, oxidative stress, osmolarity shock, inflammatory stimuli by Toll-like receptor (TLR) ligands and cytokines, withdrawal of trophic factors, chemotherapeutic drugs, and others [1,2]
JNK2β2); and two JNK3 isoforms (JNK3α1 and JNK3α2) [3]. These isoforms are divided into two groups based on differences in molecular weight: JNK1α1, JNK1β1, JNK2α1, JNK2β1, and JNK3α1 have a molecular weight of 46 kDa, and JNK1α2, JNK1β2, JNK2α2, JNK2β2, and JNK3α2 have a molecular weight of 54 kDa, with an extended C-terminus
EMT in lung fibrosis as follows: (1) using mouse tracheal epithelial cells from wild-type (WT), JNK1−/−, or JNK2−/− mice, the finding that JNK1 but not JNK2 is required for TGF-β1-induced EMT was shown [62]; (2) accumulated subepithelial collagen deposition associated with the induction of profibrotic molecules, including TGF-β1, in response to a sensitization/challenge with OVA was less in JNK1−/− mice than in WT mice
Summary
The stress-activated protein kinase (SAPK) group of mitogen-activated protein kinases (MAPKs) are Ser/Thr kinases and include two members of the c-Jun NH2-terminal kinase (JNK) and p38 MAPK families, which are activated in response to environmental stresses such as UV irradiation, oxidative stress, osmolarity shock, inflammatory stimuli by Toll-like receptor (TLR) ligands and cytokines, withdrawal of trophic factors, chemotherapeutic drugs, and others [1,2]. JNK1 was originally identified as a specific kinase for c-Jun, which is a key component of activating protein-1, a transcription factor. Subsequent analyses have revealed that JNKs regulate their various substrates, including transcription factors (β-catenin, Elk1/3/4, FOXO3/4, Jun dimerization protein (JDP) 2, JunD, Myc, neural retina leucine zipper, nuclear factor of activated T cells (NFATc) 2, nuclear receptor 4A1, p53, retinoic acid receptor-α (RARA), Sirtuin, STAT1/3, Smad2/3, etc.); kinases TAK1, a MAPK3Ks originally identified as a protein kinas by As. TGF-β bone morphogenic proteins, been binds subsequently a new and p38 activation pathway, the finding that TAB1has selectively to p38α and demo upregulates its autophosphorylation has been reported [12]. (NFκB) kinase β and MAP2K, including MKK3, MKK4, MKK6, and MKK7, resulting in TGF-β1 is known to be a key profibrotic cytokine in the pathogenesis o the activation of NFκB and SAPKs (JNK and p38) [15,16]. Schematic simplified representation of the JNK and p38 pathways mammals
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