c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis

Han, Zhen; Boyle, David L.; Chang, Louise; Bennett, Brydon L.; Karin, Michael; Yang, Li; Manning, Anthony M.; Firestein, Gary S.

doi:10.1172/jci12466

Cited by 704 publications

(212 citation statements)

References 33 publications

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“…The genome-wide expression analysis of JAK1-knockout mammary glands and control tissues revealed a number of novel target genes that were upregulated during involution in a JAK1-dependent manner. These included Runx1 and c-Fos, which was identified to be one of the first cytokine-induced proto-oncogenes (55) that can mediate tissue remodeling through expression of metalloproteinases (56,57). Other potential targets of JAK1 that were previously linked to cell death were the death receptor 6 gene (Tnfrsf21) and the tumor susceptibility gene Tpl2 (Map3k8), whose biological functions in the mammary gland have not yet been determined.…”

Section: Discussionmentioning

confidence: 99%

Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling

Sakamoto

Wehde

Yoo

et al. 2016

Molecular and Cellular Biology

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Despite a wealth of knowledge about the significance of individual signal transducers and activators of transcription (STATs), essential functions of their upstream Janus kinases (JAKs) during postnatal development are less well defined. Using a novel mammary gland-specific JAK1 knockout model, we demonstrate here that this tyrosine kinase is essential for the activation of STAT1, STAT3, and STAT6 in the mammary epithelium. The loss of JAK1 uncouples interleukin-6-class ligands from their downstream effector, STAT3, which leads to the decreased expression of STAT3 target genes that are associated with the acutephase response, inflammation, and wound healing. Consequently, JAK1-deficient mice exhibit impaired apoptosis and a significant delay in mammary gland remodeling. Using RNA sequencing, we identified several new JAK1 target genes that are upregulated during involution. These include Bmf and Bim, which are known regulators of programmed cell death. Using a BMF/BIMdouble-knockout epithelial transplant model, we further validated that the synergistic action of these proapoptotic JAK1 targets is obligatory for the remodeling of the mammary epithelium. The collective results of this study suggest that JAK1 has nonredundant roles in the activation of particular STAT proteins and this tyrosine kinase is essential for coupling inflammatory cytokine signals to the cell death machinery in the differentiated mammary epithelium.T he postnatal growth, functional differentiation, and postlactational remodeling of the epithelial compartment of the mammary gland are controlled by hormones and locally synthesized cytokines (1). While estrogen is primarily required for the elongation of mammary ducts after the onset of puberty (2, 3), progesterone and prolactin orchestrate the specification, proliferation, and differentiation of secretory alveolar cells during pregnancy (4-6). Following lactation and the weaning of the young, circulating levels of prolactin (PRL) decline and milk stasis induces the local production of interleukin-6 (IL-6)-class cytokines, in particular, IL-6, leukemia inhibitory factor (LIF), and oncostatin M (OSM). These IL-6-class cytokines trigger a cascade of intracellular events that orchestrate a process known as mammary gland remodeling, which entails the death and selective removal of terminally differentiated alveolar cells (7-9).PRL and IL-6-class cytokines signal through their corresponding receptors and utilize Janus kinases (JAKs) to activate downstream signal transducers and activators of transcription (STATs) that subsequently alter the transcriptional profile, growth, and homeostasis of mammary epithelial cells. Five of the seven STAT proteins that are known in mammals (i.e., STAT1, STAT3, STAT5a, STAT5b, and STAT6) have been found to be sequentially activated at defined stages of mammary gland development (10, 11). The levels of phosphorylated STAT1 have been reported to be elevated in nulliparous females, but this particular transcription factor seems to be largely dispensable for normal ma...

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Section: Discussionmentioning

confidence: 99%

Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling

Sakamoto

Wehde

Yoo

et al. 2016

Molecular and Cellular Biology

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“…Treatment of mice with IL-35 reduced disease severity which was associated with reduction in IL-17, IFN-γ, and an increase in IL-10 production [193] . Small molecular inhibitors of intracellular signalling: Small molecular inhibitors of intracellular signalling (e.g., NF-κB and associated activator molecules) are in focus of numerous clinical and preclinical research and have shown promising results in animal models [194,195] . RANKL inhibition : Denosumab, a human anti-RANKL mAb is approved in the United States for the treatment of postmenopausal osteoporosis but is not currently indicated for the treatment of RA (phase 2).…”

Section: Il-2 Superfamilymentioning

confidence: 99%

Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications

Magyari

Várszegi

Kövesdi

et al. 2014

WJO

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Rheumatoid arthritis (RA) is an autoimmune disease, resulting in a chronic, systemic inflammatory disorder. It may affect many tissues and organs, but it primarily affects the flexible joints. In clinical practice patient care generates many questions about diagnosis, prognosis, and treatment. It is challenging for health care specialists to keep up to date with the medical literature. This review summarizes the pathogenesis, the polymorphisms of interleukin and interleukin genes and the standard available and possible future immunologic targets for RA treatment. The identification of diseaseassociated interleukin and interleukin receptor genes can provide precious insight into the genetic variations prior to disease onset in order to identify the pathways important for RA pathogenesis. The knowledge of the complex genetic background may prove useful for developing novel therapies and making personalized medicine based on the individual's genetics.

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“…Moreover, more specific, orally active p38 inhibitors were also effective in animal models of inflammatory arthritis (44,45), presumably by blocking MMP synthesis. The MAPK c-Jun N-terminal kinase (JNK) is also important for MMP regulation; JNK is required for MMP-13 induction in chondrocytes and synoviocytes (41,46). Furthermore, inhibition of JNK by the novel inhibitor SP 600125 inhibited bone destruction in adjuvant-induced arthritis (46).…”

Section: Therapeutic Inhibition Of Mmp Gene Expressionmentioning

confidence: 99%

“…The MAPK c-Jun N-terminal kinase (JNK) is also important for MMP regulation; JNK is required for MMP-13 induction in chondrocytes and synoviocytes (41,46). Furthermore, inhibition of JNK by the novel inhibitor SP 600125 inhibited bone destruction in adjuvant-induced arthritis (46).…”

Section: Therapeutic Inhibition Of Mmp Gene Expressionmentioning

confidence: 99%

Matrix metalloproteinases as therapeutic targets in arthritic diseases: Bull's-eye or missing the mark?

Mengshol

Mix

Brinckerhoff

2002

Arthritis & Rheumatism

156

133

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c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis

Cited by 704 publications

References 33 publications

Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling

Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling

Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications

Matrix metalloproteinases as therapeutic targets in arthritic diseases: Bull's-eye or missing the mark?

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