Selective Immunomodulation of Inflammatory Pathways in Keratinocytes by the Janus Kinase (JAK) Inhibitor Tofacitinib: Implications for the Employment of JAK-Targeting Drugs in Psoriasis
Joint Authors
Facchiano, Francesco
Morelli, Martina
Mercurio, Laura
Pallotta, Sabatino
Girolomoni, Giampiero
Albanesi, Cristina
Madonna, Stefania
Scarponi, Claudia
Source
Journal of Immunology Research
Issue
Vol. 2018, Issue 2018 (31 Dec. 2018), pp.1-18, 18 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2018-11-19
Country of Publication
Egypt
No. of Pages
18
Main Subjects
Abstract EN
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.
American Psychological Association (APA)
Morelli, Martina& Scarponi, Claudia& Mercurio, Laura& Facchiano, Francesco& Pallotta, Sabatino& Madonna, Stefania…[et al.]. 2018. 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،Vol. 2018, no. 2018, pp.1-18.
https://search.emarefa.net/detail/BIM-1193030
Modern Language Association (MLA)
Morelli, Martina…[et al.]. 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 No. 2018 (2018), pp.1-18.
https://search.emarefa.net/detail/BIM-1193030
American Medical Association (AMA)
Morelli, Martina& Scarponi, Claudia& Mercurio, Laura& Facchiano, Francesco& Pallotta, Sabatino& Madonna, Stefania…[et al.]. 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. 2018. Vol. 2018, no. 2018, pp.1-18.
https://search.emarefa.net/detail/BIM-1193030
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1193030