JAK-STAT signaling in inflammation and stress-related diseases: implications for therapeutic interventions

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Abstract

The Janus kinase-signal transducer and transcription activator pathway (JAK-STAT) serves as a cornerstone in cellular signaling, regulating physiological and pathological processes such as inflammation and stress. Dysregulation in this pathway can lead to severe immunodeficiencies and malignancies, and its role extends to neurotransduction and pro-inflammatory signaling mechanisms. Although JAK inhibitors (Jakinibs) have successfully treated immunological and inflammatory disorders, their application has generally been limited to diseases with similar pathogenic features. Despite the modest expression of JAK-STAT in the CNS, it is crucial for functions in the cortex, hippocampus, and cerebellum, making it relevant in conditions like Parkinson's disease and other neuroinflammatory disorders. Furthermore, the influence of the pathway on serotonin receptors and phospholipase C has implications for stress and mood disorders. This review expands the understanding of JAK-STAT, moving beyond traditional immunological contexts to explore its role in stress-related disorders and CNS function. Recent findings, such as the effectiveness of Jakinibs in chronic conditions such as rheumatoid arthritis, expand their therapeutic applicability. Advances in isoform-specific inhibitors, including filgotinib and upadacitinib, promise greater specificity with fewer off-target effects. Combination therapies, involving Jakinibs and monoclonal antibodies, aiming to enhance therapeutic specificity and efficacy also give great hope. Overall, this review bridges the gap between basic science and clinical application, elucidating the complex influence of the JAK-STAT pathway on human health and guiding future interventions.

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Supplementary Information

The online version contains supplementary material available at 10.1186/s43556-023-00151-1.

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Targeting the IL-6/JAK/STAT3 signalling axis in cancer

Daniel E. Johnson, Jennifer R. Grandis, Rachel A O'Keefe (2018)

The IL-6/JAK/STAT3 pathway is aberrantly hyperactivated in many types of cancer, and such hyperactivation is generally associated with a poor clinical prognosis. In the tumour microenvironment, IL-6/JAK/STAT3 signalling acts to drive the proliferation, survival, invasiveness, and metastasis of tumour cells, while strongly suppressing the antitumour immune response. Thus, treatments that target the IL-6/JAK/STAT3 pathway in patients with cancer are poised to provide therapeutic benefit by directly inhibiting tumour cell growth and by stimulating antitumour immunity. Agents targeting IL-6, the IL-6 receptor, or JAKs have already received FDA approval for the treatment of inflammatory conditions or myeloproliferative neoplasms and for the management of certain adverse effects of chimeric antigen receptor T cells, and are being further evaluated in patients with haematopoietic malignancies and in those with solid tumours. Novel inhibitors of the IL-6/JAK/STAT3 pathway, including STAT3-selective inhibitors, are currently in development. Herein, we review the role of IL-6/JAK/STAT3 signalling in the tumour microenvironment and the status of preclinical and clinical investigations of agents targeting this pathway. We also discuss the potential of combining IL-6/JAK/STAT3 inhibitors with currently approved therapeutic agents directed against immune-checkpoint inhibitors.

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Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.

Dennis J Slamon, Brian Leyland-Jones, Steven Shak … (2001)

The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide alone (138 women) or with trastuzumab (143 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 vs. 4.6 months; P<0.001), a higher rate of objective response (50 percent vs. 32 percent, P<0.001), a longer duration of response (median, 9.1 vs. 6.1 months; P<0.001), a lower rate of death at 1 year (22 percent vs. 33 percent, P=0.008), longer survival (median survival, 25.1 vs. 20.3 months; P=0.01), and a 20 percent reduction in the risk of death. The most important adverse event was cardiac dysfunction of New York Heart Association class III or IV, which occurred in 27 percent of the group given an anthracycline, cyclophosphamide, and trastuzumab; 8 percent of the group given an anthracycline and cyclophosphamide alone; 13 percent of the group given paclitaxel and trastuzumab; and 1 percent of the group given paclitaxel alone. Although the cardiotoxicity was potentially severe and, in some cases, life-threatening, the symptoms generally improved with standard medical management. Trastuzumab increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2.

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Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression.

Andrew Miller, Vladimir Maletic, Charles L. Raison (2009)

Recognition that inflammation may represent a common mechanism of disease has been extended to include neuropsychiatric disorders including major depression. Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers, including inflammatory cytokines, which have been shown to access the brain and interact with virtually every pathophysiologic domain known to be involved in depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity. Indeed, activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with neuropathologic findings that characterize depressive disorders. Further instantiating the link between inflammation and depression are data demonstrating that psychosocial stress, a well-known precipitant of mood disorders, is capable of stimulating inflammatory signaling molecules, including nuclear factor kappa B, in part, through activation of sympathetic nervous system outflow pathways. Interestingly, depressed patients with increased inflammatory biomarkers have been found to be more likely to exhibit treatment resistance, and in several studies, antidepressant therapy has been associated with decreased inflammatory responses. Finally, preliminary data from patients with inflammatory disorders, as well as medically healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication. Translational implications of these findings include the unique opportunity to identify relevant patient populations, apply immune-targeted therapies, and monitor therapeutic efficacy at the level of the immune system in addition to behavior.

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Author and article information

Contributors

Alexey Sarapultsev:

ORCID: http://orcid.org/0000-0003-3101-9655

a.sarapultsev@gmail.com

Journal

Journal ID (nlm-ta): Mol Biomed

Journal ID (iso-abbrev): Mol Biomed

Title: Molecular Biomedicine

Publisher: Springer Nature Singapore (Singapore )

ISSN (Electronic): 2662-8651

Publication date (Electronic): 8 November 2023

Publication date PMC-release: 8 November 2023

Publication date Collection: December 2023

Volume: 4

Electronic Location Identifier: 40

Affiliations

[1 ]Russian-Chinese Education and Research Center of System Pathology, South Ural State University, ( https://ror.org/03sfk2504) 454080 Chelyabinsk, Russia

[2 ]GRID grid.426536.0, ISNI 0000 0004 1760 306X, Institute of Immunology and Physiology, , Ural Branch of the Russian Academy of Science, ; 620049 Ekaterinburg, Russia

[3 ]Department of Organic and Biomolecular Chemistry, Ural Federal University, ( https://ror.org/00hs7dr46) 620002 Ekaterinburg, Russian Federation

[4 ]GRID grid.412839.5, ISNI 0000 0004 1771 3250, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, ; Wuhan, 430022 China

[5 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of Integrated Traditional Chinese and Western Medicine, , Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, ; Wuhan, 430022 China

[6 ]GRID grid.419897.a, ISNI 0000 0004 0369 313X, Key Laboratory of Biological Targeted Therapy, , The Ministry of Education, ; Wuhan, 430022 China

[7 ]GRID grid.452344.0, Clinical Research Center of Cancer Immunotherapy, ; Hubei Wuhan, 430022 China

Author information

Alexey Sarapultsev http://orcid.org/0000-0003-3101-9655

Article

Publisher ID: 151

DOI: 10.1186/s43556-023-00151-1

PMC ID: 10632324

PubMed ID: 37938494

SO-VID: 69a8595a-ef17-4a8b-9e98-d87fec5242ae

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 14 July 2023

Date accepted : 26 October 2023

Funding

Funded by: South Ural State University

Award ID: FENU-2023-0014

Award Recipient : Alexey Sarapultsev Maria Komelkova Irina Utepova

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Keywords: inflammation,jak inhibitors,jak-stat signaling,neuropsychiatric disorders,stress-related conditions,therapeutic advancements

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Keywords: inflammation, jak inhibitors, jak-stat signaling, neuropsychiatric disorders, stress-related conditions, therapeutic advancements

JAK-STAT signaling in inflammation and stress-related diseases: implications for therapeutic interventions

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Most cited references 315

Targeting the IL-6/JAK/STAT3 signalling axis in cancer

Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.

Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression.

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