Spleen tyrosine kinase inhibition in the treatment of autoimmune, allergic and autoinflammatory diseases

Pamuk, Ömer Nurı; Tsokos, George C.

doi:10.1186/ar3198

Cited by 70 publications

(65 citation statements)

References 64 publications

(100 reference statements)

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“…These observations open the possibility that IL-21, in mononuclear cells, exerts functions other than phagocytosis, which involve the participation of Syk, an enzyme that is becoming recognized to play crucial roles in several biological functions (40). Moreover, knowing that targeting Syk is relevant to the treatment of inflammatory diseases (41)(42)(43), and because IL-21 is associated with a variety of inflammatory disorders, including psoriasis, systemic lupus erythematosus, and arthritis (44)(45)(46), our results support the targeting of the IL-21/IL-21R system for the development of therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

IL-21 Enhances Phagocytosis in Mononuclear Phagocyte Cells: Identification of Spleen Tyrosine Kinase as a Novel Molecular Target of IL-21

Vallières

Girard

2013

The Journal of Immunology

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The biological significance of the IL-21/IL-21R system in human monocytes/macrophages is not well documented, and the expression of IL-21R is unclear and has been disputed. In this study, we showed for the first time, to our knowledge, that human monocyte–like THP-1 cells expressed the two IL-21R components, CD132 (γc) and IL-21Rα, on their cell surface, as assessed by flow cytometry. Moreover, IL-21 was found to enhance FcR-mediated phagocytosis, but not endocytosis. The ability of IL-21 to enhance phagocytosis was not associated with an increased expression of both IL-21R components at the cell surface, and IL-21 did not act in synergy with IL-15. IL-21 activated spleen tyrosine kinase (Syk), as evidenced by its ability to increase Syk phosphorylation. Using a pharmacological approach to inhibit Syk activity, and an antisense technique to downregulate Syk protein expression, we demonstrated the importance of Syk in IL-21–induced phagocytosis. In addition, both CD132 and IL-21Rα were expressed on the cell surface of naive monocytes, as well as in GM-CSF–monocyte-derived macrophages. Moreover, IL-21 also induced phagocytosis in these cells. We conclude that IL-21 possesses important biological effects in mononuclear phagocyte cells and that Syk is a novel molecular target of IL-21 that was previously unknown. Therefore, future development of therapeutic strategies targeting the IL-21/IL-21R system should consider that monocyte and macrophage cell physiology may be affected by this system.

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Section: Discussionmentioning

confidence: 99%

IL-21 Enhances Phagocytosis in Mononuclear Phagocyte Cells: Identification of Spleen Tyrosine Kinase as a Novel Molecular Target of IL-21

Vallières

Girard

2013

The Journal of Immunology

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“…However, little is known about whether Syk participates in IL-17R signaling or not. Notably, recent studies have raised attention on Syk as a promising therapeutic target, and many clinical trials for Syk inhibitors in several autoimmune diseases such as rheumatoid arthritis, asthma, and allergic rhinitis are undergoing (Meltzer et al, 2005;Mocsai et al, 2010;Pamuk and Tsokos, 2010;Riccaboni et al, 2010) IL-17R-proximal signaling complex (IL-17R-Act1-TRAF6) is essential for IL-17A-mediated NF-kB activation. Here using pharmacological and genetic approaches we demonstrated that Syk is a mediator for the complex formation.…”

Section: Discussionmentioning

confidence: 99%

Syk Mediates IL−17-Induced CCL20 Expression by Targeting Act1-Dependent K63-Linked Ubiquitination of TRAF6

Huang

Tsou

et al. 2015

Journal of Investigative Dermatology

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IL-17 has an important role in the immunopathogenesis of autoimmune diseases, and spleen tyrosine kinase (Syk) has been implicated as a critical molecule in the signaling pathways of various immunoreceptors. Chemokine (C-C motif) ligand 20 (CCL20) interacts with chemokine (C-C motif) receptor 6 to recruit IL-17-producing cells into the skin to promote progression of psoriasis. Herein we investigate how Syk regulates IL-17 signaling to affect CCL20 expression in primary human epidermal keratinocytes. We found that IL-17 can induce CCL20 expression and activate TAK, IKK, NF-κB, c-Jun N-terminal kinase, and Syk. Data of TAK inhibitor and Syk small interfering RNA (siRNA) indicate Syk being an upstream molecule of TAK in IL-17-elicited signaling. The promoter activity assay combined with site-directed mutagenesis showed that IL-17-elicited CCL20 upregulation is depending on the Syk-mediated NF-κB pathway. Immunoprecipitation also indicated the interaction of Syk with signal molecules of IL-17R, such as TRAF6 and Act1, under IL-17A stimulation. However, the essential signaling events including TRAF6 interaction with Act1 and TRAF6 polyubiquitination under IL-17A stimulation were diminished by Syk siRNA and pharmacologically inhibiting Syk. Taken together, we identify Syk as an upstream signaling molecule in IL-17A-induced Act1-TRAF6 interaction in keratinocytes, and inhibition of Syk can attenuate CCL20 production, which highlights Syk as a potential therapeutic target for inflammatory skin diseases such as psoriasis.

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“…Small-molecule inhibitors of SYK activity suppress disease in a number of inflammatory disease models. 76 SYK can be detected in the skin lesions of MRL/lpr mice, 77 and treatment with a SYK inhibitor can abrogate the development of skin lesions induced by intradermal injection of lupus IgG in MRL/lpr mice, as well as suppress established skin lesions in such mice. 77 In addition, inhibition of SYK can result in the disappearance of established skin lesions in BAK -/-BAX -/-double-knockout mice, which spontaneously develop inflammatory skin lesions.…”

Section: Sykmentioning

confidence: 99%

Pathogenesis and targeted treatment of skin injury in SLE

Deng

Tsokos

2015

Nat Rev Rheumatol

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Skin is the second most common organ (after the kidney) to be affected in patients with systemic lupus erythematosus (SLE), yet the aetiology of skin injury and the mechanisms involved in the development of dermal manifestations of SLE remain unclear. Ultraviolet light (UV), immune cells, cytokines and deposition of immunoglobulins all seem to have a role in the development of skin inflammation and damage in SLE. UV represents the most important environmental factor, and exposure to UV triggers the development of skin lesions in areas where immunoglobulin has been deposited and various other components of the immune system have accumulated. In addition, a number of intracellular kinases and transcription factors have also been demonstrated to be involved in the generation of skin lesions in lupus-prone mice. These molecules can be targeted by small-molecule inhibitors, leading to the prospect that treatments suitable for topical application, and with limited adverse effects, could be developed. Further studies to eliminate the burden of skin inflammation in patients with SLE are clearly required.

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Spleen tyrosine kinase inhibition in the treatment of autoimmune, allergic and autoinflammatory diseases

Cited by 70 publications

References 64 publications

IL-21 Enhances Phagocytosis in Mononuclear Phagocyte Cells: Identification of Spleen Tyrosine Kinase as a Novel Molecular Target of IL-21

IL-21 Enhances Phagocytosis in Mononuclear Phagocyte Cells: Identification of Spleen Tyrosine Kinase as a Novel Molecular Target of IL-21

Syk Mediates IL−17-Induced CCL20 Expression by Targeting Act1-Dependent K63-Linked Ubiquitination of TRAF6

Pathogenesis and targeted treatment of skin injury in SLE

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