Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition
Rheumatoid arthritis (RA) is a chronic inflammatory disorder that causes joint pain, swelling, and loss of function. Development of effective new drugs has proven challenging in part because of the complexities and interconnected nature of intracellular signaling networks that complicate the effects...
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| Materyal Türü: | Makale |
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American Association for the Advancement of Science
2018
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| Online Erişim: | http://hdl.handle.net/1721.1/117688 https://orcid.org/0000-0003-1022-9450 https://orcid.org/0000-0002-0050-989X |
| _version_ | 1826216443576844288 |
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| author | Jenney, Anne P. Sorger, Peter K. Jones II, Douglas S. Joughin, Brian Alan Lauffenburger, Douglas A |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Jenney, Anne P. Sorger, Peter K. Jones II, Douglas S. Joughin, Brian Alan Lauffenburger, Douglas A |
| author_sort | Jenney, Anne P. |
| collection | MIT |
| description | Rheumatoid arthritis (RA) is a chronic inflammatory disorder that causes joint pain, swelling, and loss of function. Development of effective new drugs has proven challenging in part because of the complexities and interconnected nature of intracellular signaling networks that complicate the effects of pharmacological interventions. We characterized the kinase signaling pathways that are activated in RA and evaluated the multivariate effects of targeted inhibitors. Synovial fluids from RA patients activated the kinase signaling pathways JAK, JNK, p38, and MEK in synovial fibroblasts (SFs), a stromal cell type that promotes RA progression. Kinase inhibitors enhanced signaling of “off-target” pathways in a manner dependent on stimulatory context. Inhibitors of p38, which have been widely explored in clinical trials for RA, resulted in undesirable increases in nuclear factor B (NF-B), JNK, and MEK signaling in SFs in inflammatory, but not mitogenic, contexts. This was mediated by the transcription factor CREB, which functions in part within a negative feedback loop in MAPK signaling. CREB activation was induced predominately by p38 in response to inflammatory stimuli, but by MEK in response to mitogenic stimuli; hence, the effects of drugs targeting p38 or MEK were markedly different in SFs cultured under mitogenic or inflammatory conditions. Together, these findings illustrate how stimulatory context can alter dominance in pathway cross-talk even for a fixed network topology, thereby providing a rationale for why p38 inhibitors deliver limited benefits in RA and demonstrating the need for careful consideration of p38-targeted drugs in inflammation-related disorders. |
| first_indexed | 2024-09-23T16:47:46Z |
| format | Article |
| id | mit-1721.1/117688 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T16:47:46Z |
| publishDate | 2018 |
| publisher | American Association for the Advancement of Science |
| record_format | dspace |
| spelling | mit-1721.1/1176882022-10-03T08:23:00Z Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition Jenney, Anne P. Sorger, Peter K. Jones II, Douglas S. Joughin, Brian Alan Lauffenburger, Douglas A Massachusetts Institute of Technology. Department of Biological Engineering Koch Institute for Integrative Cancer Research at MIT Jones II, Douglas S. Joughin, Brian Alan Lauffenburger, Douglas A Rheumatoid arthritis (RA) is a chronic inflammatory disorder that causes joint pain, swelling, and loss of function. Development of effective new drugs has proven challenging in part because of the complexities and interconnected nature of intracellular signaling networks that complicate the effects of pharmacological interventions. We characterized the kinase signaling pathways that are activated in RA and evaluated the multivariate effects of targeted inhibitors. Synovial fluids from RA patients activated the kinase signaling pathways JAK, JNK, p38, and MEK in synovial fibroblasts (SFs), a stromal cell type that promotes RA progression. Kinase inhibitors enhanced signaling of “off-target” pathways in a manner dependent on stimulatory context. Inhibitors of p38, which have been widely explored in clinical trials for RA, resulted in undesirable increases in nuclear factor B (NF-B), JNK, and MEK signaling in SFs in inflammatory, but not mitogenic, contexts. This was mediated by the transcription factor CREB, which functions in part within a negative feedback loop in MAPK signaling. CREB activation was induced predominately by p38 in response to inflammatory stimuli, but by MEK in response to mitogenic stimuli; hence, the effects of drugs targeting p38 or MEK were markedly different in SFs cultured under mitogenic or inflammatory conditions. Together, these findings illustrate how stimulatory context can alter dominance in pathway cross-talk even for a fixed network topology, thereby providing a rationale for why p38 inhibitors deliver limited benefits in RA and demonstrating the need for careful consideration of p38-targeted drugs in inflammation-related disorders. National Institutes of Health (U.S.) (Grant U54HL127365) National Institutes of Health (U.S.) (Grant P50GM107618) United States. Army Research Office (Grant W911NF-09-0001) National Institutes of Health (U.S.) (Grant 5F32AR062931) 2018-09-10T18:43:03Z 2018-09-10T18:43:03Z 2018-03 2016-10 2018-09-07T18:34:45Z Article http://purl.org/eprint/type/JournalArticle 1945-0877 1937-9145 http://hdl.handle.net/1721.1/117688 Jones, Douglas S. et al. “Inflammatory but Not Mitogenic Contexts Prime Synovial Fibroblasts for Compensatory Signaling Responses to P38 Inhibition.” Science Signaling 11, 520 (March 2018): eaal1601 © 2018 The Authors https://orcid.org/0000-0003-1022-9450 https://orcid.org/0000-0002-0050-989X http://dx.doi.org/10.1126/scisignal.aal1601 Science Signaling Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Association for the Advancement of Science PMC |
| spellingShingle | Jenney, Anne P. Sorger, Peter K. Jones II, Douglas S. Joughin, Brian Alan Lauffenburger, Douglas A Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition |
| title | Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition |
| title_full | Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition |
| title_fullStr | Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition |
| title_full_unstemmed | Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition |
| title_short | Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition |
| title_sort | inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition |
| url | http://hdl.handle.net/1721.1/117688 https://orcid.org/0000-0003-1022-9450 https://orcid.org/0000-0002-0050-989X |
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