Delineation of the distinct inflammatory signaling roles of TAK1 and JAK1/3 in the CIA model of rheumatoid arthritis
Abstract Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by hyperactive immune cells within the joints, which leads to inflammation, bone degeneration, and chronic pain. For several decades, frontline immunomodulators such as the anti‐tumor necrosis factor (TNF) biologics ada...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-08-01
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| Series: | Pharmacology Research & Perspectives |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/prp2.1124 |
| _version_ | 1797743660117262336 |
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| author | Robert Freeze Kelly W. Yang Timothy Haystead Philip Hughes Scott Scarneo |
| author_facet | Robert Freeze Kelly W. Yang Timothy Haystead Philip Hughes Scott Scarneo |
| author_sort | Robert Freeze |
| collection | DOAJ |
| description | Abstract Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by hyperactive immune cells within the joints, which leads to inflammation, bone degeneration, and chronic pain. For several decades, frontline immunomodulators such as the anti‐tumor necrosis factor (TNF) biologics adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade) have successfully managed disease progression for many patients. However, over time, patients become refractory to these treatments requiring chronic disease to be managed with conventional and more problematic disease modifying antirheumatic drugs such as methotrexate and hydroxychloroquine, and corticosteroids. Due to the large proportion of patients who continue to fail on frontline biologic therapies, there remains an unmet need to derive novel alternative targets with improved efficacy and safety profiles to treat RA. Recent advances in the field have defined novel targets that play important roles in RA pathology, including the Janus activated kinase (JAK) and transforming growth factor beta activated kinase‐1 (TAK1). Although three inhibitors of the JAK signaling pathway have been approved for the treatment of moderately to severely active RA in patients who failed on one or more anti‐TNFs, at present, no FDA approved TAK1 treatments exist. Our recent discovery of a highly potent and selective, orally bioavailable TAK1 inhibitor has provided insight into the therapeutic potential of this protein kinase as a novel target for RA. Here, we show the distinct cytokine signaling of tofacitnib (Xeljanz; JAK1/3 inhibitor) compared to HS‐276 (TAK1 inhibitor) in lipopolysaccharide (LPS) challenged THP‐1 cells. Furthermore, in the collagen induced arthritis pre‐clinical mouse model of RA, both tofacintib and HS‐276 attenuated disease activity score and inflammatory cytokines in the serum. Overall, our results delineate the distinct cytokine signaling of JAK1/3 and TAK1 targeted therapies in vitro and in vivo and suggest that selective TAK1 inhibitors may provide superior therapeutic relief in RA with fewer adverse events. |
| first_indexed | 2024-03-12T14:58:36Z |
| format | Article |
| id | doaj.art-7a457dbbab1640ecab5641b20178e6cc |
| institution | Directory Open Access Journal |
| issn | 2052-1707 |
| language | English |
| last_indexed | 2024-03-12T14:58:36Z |
| publishDate | 2023-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj.art-7a457dbbab1640ecab5641b20178e6cc2023-08-14T10:06:45ZengWileyPharmacology Research & Perspectives2052-17072023-08-01114n/an/a10.1002/prp2.1124Delineation of the distinct inflammatory signaling roles of TAK1 and JAK1/3 in the CIA model of rheumatoid arthritisRobert Freeze0Kelly W. Yang1Timothy Haystead2Philip Hughes3Scott Scarneo4EydisBio, Inc. Durham North Carolina USADepartment of Pharmacology and Cancer Biology Duke University School of Medicine Durham North Carolina USAEydisBio, Inc. Durham North Carolina USAEydisBio, Inc. Durham North Carolina USAEydisBio, Inc. Durham North Carolina USAAbstract Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by hyperactive immune cells within the joints, which leads to inflammation, bone degeneration, and chronic pain. For several decades, frontline immunomodulators such as the anti‐tumor necrosis factor (TNF) biologics adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade) have successfully managed disease progression for many patients. However, over time, patients become refractory to these treatments requiring chronic disease to be managed with conventional and more problematic disease modifying antirheumatic drugs such as methotrexate and hydroxychloroquine, and corticosteroids. Due to the large proportion of patients who continue to fail on frontline biologic therapies, there remains an unmet need to derive novel alternative targets with improved efficacy and safety profiles to treat RA. Recent advances in the field have defined novel targets that play important roles in RA pathology, including the Janus activated kinase (JAK) and transforming growth factor beta activated kinase‐1 (TAK1). Although three inhibitors of the JAK signaling pathway have been approved for the treatment of moderately to severely active RA in patients who failed on one or more anti‐TNFs, at present, no FDA approved TAK1 treatments exist. Our recent discovery of a highly potent and selective, orally bioavailable TAK1 inhibitor has provided insight into the therapeutic potential of this protein kinase as a novel target for RA. Here, we show the distinct cytokine signaling of tofacitnib (Xeljanz; JAK1/3 inhibitor) compared to HS‐276 (TAK1 inhibitor) in lipopolysaccharide (LPS) challenged THP‐1 cells. Furthermore, in the collagen induced arthritis pre‐clinical mouse model of RA, both tofacintib and HS‐276 attenuated disease activity score and inflammatory cytokines in the serum. Overall, our results delineate the distinct cytokine signaling of JAK1/3 and TAK1 targeted therapies in vitro and in vivo and suggest that selective TAK1 inhibitors may provide superior therapeutic relief in RA with fewer adverse events.https://doi.org/10.1002/prp2.1124inflammationrheumatoid arthritissmall moleculeTAK1therapeuticsTNF |
| spellingShingle | Robert Freeze Kelly W. Yang Timothy Haystead Philip Hughes Scott Scarneo Delineation of the distinct inflammatory signaling roles of TAK1 and JAK1/3 in the CIA model of rheumatoid arthritis Pharmacology Research & Perspectives inflammation rheumatoid arthritis small molecule TAK1 therapeutics TNF |
| title | Delineation of the distinct inflammatory signaling roles of TAK1 and JAK1/3 in the CIA model of rheumatoid arthritis |
| title_full | Delineation of the distinct inflammatory signaling roles of TAK1 and JAK1/3 in the CIA model of rheumatoid arthritis |
| title_fullStr | Delineation of the distinct inflammatory signaling roles of TAK1 and JAK1/3 in the CIA model of rheumatoid arthritis |
| title_full_unstemmed | Delineation of the distinct inflammatory signaling roles of TAK1 and JAK1/3 in the CIA model of rheumatoid arthritis |
| title_short | Delineation of the distinct inflammatory signaling roles of TAK1 and JAK1/3 in the CIA model of rheumatoid arthritis |
| title_sort | delineation of the distinct inflammatory signaling roles of tak1 and jak1 3 in the cia model of rheumatoid arthritis |
| topic | inflammation rheumatoid arthritis small molecule TAK1 therapeutics TNF |
| url | https://doi.org/10.1002/prp2.1124 |
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