Selective Immunomodulation of Inflammatory Pathways in Keratinocytes by the Janus Kinase (JAK) Inhibitor Tofacitinib: Implications for the Employment of JAK-Targeting Drugs in Psoriasis
IFN-γ and IL-22 are deeply involved in the pathogenesis of psoriasis, as they boost the expression of inflammatory genes and alter proliferative and differentiative programs in keratinocytes. The JAK1/JAK2/STAT1 and JAK1/TYK2/STAT3 pathways triggered by IFN-γ and IL-22, respectively, are aberrantly...
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| Format: | Article |
| Language: | English |
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2018-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2018/7897263 |
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| author | Martina Morelli Claudia Scarponi Laura Mercurio Francesco Facchiano Sabatino Pallotta Stefania Madonna Giampiero Girolomoni Cristina Albanesi |
| author_facet | Martina Morelli Claudia Scarponi Laura Mercurio Francesco Facchiano Sabatino Pallotta Stefania Madonna Giampiero Girolomoni Cristina Albanesi |
| author_sort | Martina Morelli |
| collection | DOAJ |
| description | IFN-γ and IL-22 are deeply involved in the pathogenesis of psoriasis, as they boost the expression of inflammatory genes and alter proliferative and differentiative programs in keratinocytes. The JAK1/JAK2/STAT1 and JAK1/TYK2/STAT3 pathways triggered by IFN-γ and IL-22, respectively, are aberrantly activated in psoriasis, as highlighted by the peculiar STAT1 and STAT3 signatures in psoriatic skin lesions. To limit the detrimental consequences of IFN-γ and IL-22 excessive stimulation, psoriatic keratinocytes activate suppressor of cytokine signaling (SOCS)1 and SOCS3, which in turn dampen molecular signaling by inhibiting JAK1 and JAK2. Thus, JAK targeting appears to be a reasonable strategy to treat psoriasis. Tofacitinib is an inhibitor of JAK proteins, which, similarly to SOCS, impedes JAK phosphorylation. In this study, we evaluated the immunomodulatory effects of tofacitinib on epidermal keratinocytes in in vitro and in vivo models of psoriasis. We demonstrated the selectivity of tofacitinib inhibitory action on IFN-γ and IL-22, but not on TNF-γ or IL-17 proinflammatory signaling, with suppressed expression of IFN-γ-dependent inflammatory genes, and restoration of normal proliferative and differentiative programs altered by IL-22 in psoriatic keratinocyte cultures. Tofacitinib also potently reduced the psoriasiform phenotype in the imiquimod-induced murine model of psoriasis. Finally, we found that tofacitinib mimics SOCS1 or SOCS3 activities, as it impaired the same molecular pathways in IFN-γ or IL-22-activated keratinocytes. |
| format | Article |
| id | doaj-art-6673f14836e0496b9500aeaabf88ef28 |
| institution | Kabale University |
| issn | 2314-8861 2314-7156 |
| language | English |
| publishDate | 2018-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-6673f14836e0496b9500aeaabf88ef282025-02-03T01:02:20ZengWileyJournal of Immunology Research2314-88612314-71562018-01-01201810.1155/2018/78972637897263Selective Immunomodulation of Inflammatory Pathways in Keratinocytes by the Janus Kinase (JAK) Inhibitor Tofacitinib: Implications for the Employment of JAK-Targeting Drugs in PsoriasisMartina Morelli0Claudia Scarponi1Laura Mercurio2Francesco Facchiano3Sabatino Pallotta4Stefania Madonna5Giampiero Girolomoni6Cristina Albanesi7Section of Dermatology, Department of Medicine, University of Verona, Verona 37126, ItalyLaboratory of Experimental Immunology and V Division of Dermatology, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Rome 00167, ItalyLaboratory of Experimental Immunology and V Division of Dermatology, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Rome 00167, ItalyDepartment of Oncology and Molecular Medicine, Istituto Superiore di Sanità (ISS), Rome 00161, ItalyLaboratory of Experimental Immunology and V Division of Dermatology, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Rome 00167, ItalyLaboratory of Experimental Immunology and V Division of Dermatology, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Rome 00167, ItalySection of Dermatology, Department of Medicine, University of Verona, Verona 37126, ItalyLaboratory of Experimental Immunology and V Division of Dermatology, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Rome 00167, ItalyIFN-γ and IL-22 are deeply involved in the pathogenesis of psoriasis, as they boost the expression of inflammatory genes and alter proliferative and differentiative programs in keratinocytes. The JAK1/JAK2/STAT1 and JAK1/TYK2/STAT3 pathways triggered by IFN-γ and IL-22, respectively, are aberrantly activated in psoriasis, as highlighted by the peculiar STAT1 and STAT3 signatures in psoriatic skin lesions. To limit the detrimental consequences of IFN-γ and IL-22 excessive stimulation, psoriatic keratinocytes activate suppressor of cytokine signaling (SOCS)1 and SOCS3, which in turn dampen molecular signaling by inhibiting JAK1 and JAK2. Thus, JAK targeting appears to be a reasonable strategy to treat psoriasis. Tofacitinib is an inhibitor of JAK proteins, which, similarly to SOCS, impedes JAK phosphorylation. In this study, we evaluated the immunomodulatory effects of tofacitinib on epidermal keratinocytes in in vitro and in vivo models of psoriasis. We demonstrated the selectivity of tofacitinib inhibitory action on IFN-γ and IL-22, but not on TNF-γ or IL-17 proinflammatory signaling, with suppressed expression of IFN-γ-dependent inflammatory genes, and restoration of normal proliferative and differentiative programs altered by IL-22 in psoriatic keratinocyte cultures. Tofacitinib also potently reduced the psoriasiform phenotype in the imiquimod-induced murine model of psoriasis. Finally, we found that tofacitinib mimics SOCS1 or SOCS3 activities, as it impaired the same molecular pathways in IFN-γ or IL-22-activated keratinocytes.http://dx.doi.org/10.1155/2018/7897263 |
| spellingShingle | Martina Morelli Claudia Scarponi Laura Mercurio Francesco Facchiano Sabatino Pallotta Stefania Madonna Giampiero Girolomoni Cristina Albanesi Selective Immunomodulation of Inflammatory Pathways in Keratinocytes by the Janus Kinase (JAK) Inhibitor Tofacitinib: Implications for the Employment of JAK-Targeting Drugs in Psoriasis Journal of Immunology Research |
| title | Selective Immunomodulation of Inflammatory Pathways in Keratinocytes by the Janus Kinase (JAK) Inhibitor Tofacitinib: Implications for the Employment of JAK-Targeting Drugs in Psoriasis |
| title_full | Selective Immunomodulation of Inflammatory Pathways in Keratinocytes by the Janus Kinase (JAK) Inhibitor Tofacitinib: Implications for the Employment of JAK-Targeting Drugs in Psoriasis |
| title_fullStr | Selective Immunomodulation of Inflammatory Pathways in Keratinocytes by the Janus Kinase (JAK) Inhibitor Tofacitinib: Implications for the Employment of JAK-Targeting Drugs in Psoriasis |
| title_full_unstemmed | Selective Immunomodulation of Inflammatory Pathways in Keratinocytes by the Janus Kinase (JAK) Inhibitor Tofacitinib: Implications for the Employment of JAK-Targeting Drugs in Psoriasis |
| title_short | Selective Immunomodulation of Inflammatory Pathways in Keratinocytes by the Janus Kinase (JAK) Inhibitor Tofacitinib: Implications for the Employment of JAK-Targeting Drugs in Psoriasis |
| title_sort | selective immunomodulation of inflammatory pathways in keratinocytes by the janus kinase jak inhibitor tofacitinib implications for the employment of jak targeting drugs in psoriasis |
| url | http://dx.doi.org/10.1155/2018/7897263 |
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