| Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes. | |
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MedLine Citation:
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PMID: 19895991 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: TNF inhibitors have revolutionized the treatment of psoriasis vulgaris as well as psoriatic and rheumatoid arthritis and Crohn disease. Despite our understanding that these agents block TNF, their complex mechanism of action in disease resolution is still unclear. OBJECTIVE: To analyze globally the genomic effects of TNF inhibition in patients with psoriasis, and to compare genomic profiles of patients who responded or did not respond to treatment. METHODS: In a clinical trial using etanercept TNF inhibitor to treat psoriasis vulgaris (n = 15), Affymetrix gene arrays were used to analyze gene profiles in lesional skin at multiple time points during drug treatment (baseline and weeks 1, 2, 4, and 12) compared with nonlesional skin. Patients were stratified as responders (n = 11) or nonresponders (n = 4) on the basis of histologic disease resolution. Cluster analysis was used to define gene sets that were modulated with similar magnitude and velocity over time. RESULTS: In responders, 4 clusters of downregulated genes and 3 clusters of upregulated genes were identified. Genes downmodulated most rapidly reflected direct inhibition of myeloid lineage immune genes. Upregulated genes included the stable dendritic cell population genes CD1c and CD207 (langerin). Comparison of responders and nonresponders revealed rapid downmodulation of innate IL-1beta and IL-8 sepsis cascade cytokines in both groups, but only responders downregulated IL-17 pathway genes to baseline levels. CONCLUSION: Although both responders and nonresponders to etanercept inactivated sepsis cascade cytokines, response to etanercept is dependent on inactivation of myeloid dendritic cell genes and inactivation of the T(H)17 immune response. |
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Authors:
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Lisa C Zaba; Mayte Suárez-Fariñas; Judilyn Fuentes-Duculan; Kristine E Nograles; Emma Guttman-Yassky; Irma Cardinale; Michelle A Lowes; James G Krueger |
Publication Detail:
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Type: Clinical Trial; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of allergy and clinical immunology Volume: 124 ISSN: 1097-6825 ISO Abbreviation: J. Allergy Clin. Immunol. Publication Date: 2009 Nov |
Date Detail:
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Created Date: 2009-11-09 Completed Date: 2009-11-24 Revised Date: 2010-12-03 |
Medline Journal Info:
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Nlm Unique ID: 1275002 Medline TA: J Allergy Clin Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 1022-10.e1-395 Citation Subset: AIM; IM |
Affiliation:
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Laboratory for Investigative Dermatology, Rockefeller University, New York, NY 10065, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Anti-Inflammatory Agents, Non-Steroidal
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administration & dosage,
therapeutic use* Dendritic Cells / drug effects*, immunology, metabolism Down-Regulation / drug effects, genetics, immunology Gene Expression / drug effects Gene Expression Profiling Humans Immunoglobulin G / administration & dosage, therapeutic use* Interferon-gamma / antagonists & inhibitors, immunology, metabolism Interleukin-17 / antagonists & inhibitors, immunology*, metabolism Interleukin-1beta / antagonists & inhibitors, immunology, metabolism Interleukin-8 / antagonists & inhibitors, immunology, metabolism Myeloid Cells / drug effects*, immunology, metabolism Oligonucleotide Array Sequence Analysis Psoriasis / drug therapy*, genetics, immunology Receptors, Tumor Necrosis Factor / administration & dosage, therapeutic use* Signal Transduction Skin / drug effects, immunology, pathology T-Lymphocytes, Helper-Inducer / drug effects*, immunology, metabolism Tumor Necrosis Factor-alpha / antagonists & inhibitors Up-Regulation / drug effects, genetics, immunology |
| Grant Support | |
ID/Acronym/Agency:
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GM07739/GM/NIGMS NIH HHS; K23 AR052404-01A1/AR/NIAMS NIH HHS; M01 RR000102-410438/RR/NCRR NIH HHS; UL1RR024143/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Anti-Inflammatory Agents, Non-Steroidal; 0/Immunoglobulin G; 0/Interleukin-17; 0/Interleukin-1beta; 0/Interleukin-8; 0/Receptors, Tumor Necrosis Factor; 0/Tumor Necrosis Factor-alpha; 185243-69-0/TNFR-Fc fusion protein; 82115-62-6/Interferon-gamma |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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