IL-22 Increases the Innate Immunity of Tissues

Wolk, Kerstin; Kunz, Stefanie; Witte, Ellen; Friedrich, Markus; Asadullah, Khusru; Sabat, Robert

doi:10.1016/j.immuni.2004.07.007

Cited by 1,202 publications

(1,252 citation statements)

References 33 publications

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“…Since IL-23R expression is low in naive T cells, there are likely to be other unidentified cytokines or signals that act in conjunction with IL-23 to regulate IL-17 expression. However, in human CD4ϩ T cells, IL-23 is also an extremely potent inducer of IL-22, IFN␥, and TNF, cytokines that all participate in autoimmune diseases (12,49,50). Therefore, the concept that a major driver of autoimmune diseases can be explained solely by a discrete IL-23/IL-17 connection is likely an oversimplification in humans.…”

Section: Il-17 Regulation In Human T Cellsmentioning

confidence: 99%

Distinct regulation of interleukin‐17 in human T helper lymphocytes

Chen¹,

Tato²,

Muul³

et al. 2007

Arthritis & Rheumatism

312

278

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Section: Il-17 Regulation In Human T Cellsmentioning

confidence: 99%

Distinct regulation of interleukin‐17 in human T helper lymphocytes

Chen¹,

Tato²,

Muul³

et al. 2007

Arthritis & Rheumatism

312

278

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“…1) a heterodimeric molecule composed of the shared IL-10R2 subunit and the unique IL-22R1 subunit, and it is expressed as a functional molecule at high levels in keratinocytes and cells in the pancreas, colon, liver, kidney, lung, and stomach. However, IL-22R1 is not expressed on any immune cells and therefore has no direct effect on their activity [47]. Signaling through the IL-22 receptor in keratinocytes occurs through activation and phosphorylation of Stat3 [47,48].…”

Section: Th17 Effector Cytokines: Il-17a Il-22 and Il-21mentioning

confidence: 99%

“…However, IL-22R1 is not expressed on any immune cells and therefore has no direct effect on their activity [47]. Signaling through the IL-22 receptor in keratinocytes occurs through activation and phosphorylation of Stat3 [47,48].…”

Section: Th17 Effector Cytokines: Il-17a Il-22 and Il-21mentioning

confidence: 99%

Pathophysiology of psoriasis: Recent advances on IL-23 and Th17 cytokines

Fitch¹,

Harper²,

Skorcheva³

et al. 2007

Curr Rheumatol Rep

334

249

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T helper (Th) 17 cells, a novel T-cell subset, have been implicated in the pathogenesis of psoriasis and other autoimmune inflammatory diseases. Interleukin (IL)-23 stimulates survival and proliferation of Th17 cells, and thus serves as a key master cytokine regulator for these diseases. In psoriasis, IL-23 is overproduced by dendritic cells and keratinocytes, and this cytokine stimulates Th17 cells within dermis to make IL-17A and IL-22. IL-22, in particular, drives keratinocyte hyperproliferation in psoriasis. Future targeting of these key cytokines is likely to lead to dramatic clinical improvement in patients with psoriasis. This review focuses on the numerous recent studies on the roles of IL-23 and Th17 cells in the pathogenesis of psoriasis.

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“…IL-22 signals through IL-10R type II and IL-22R, which mediate STAT protein phosphorylation via Tyk-2 and JAK-1, respectively (29). IL-22 induces the release of acutephase reactants such as haptoglobin, SAA, and ␣ 1 -antichymotrypsin from the liver (30), and IL-22-dependent production of SAA can be detected in serum (31). An IL-22-neutralizing antibody completely blocked IL-22-mediated serum SAA production ( Figure 3B).…”

Section: In Vitro Activity Wye-151650 (mentioning

confidence: 99%

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

Lin

Hegen

Quadros

et al. 2010

Arthritis & Rheumatism

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Objective. All ␥-chain cytokines signal through JAK-3 and JAK-1 acting in tandem. We undertook this study to determine whether the JAK-3 selective inhibitor WYE-151650 would be sufficient to disrupt cytokine signaling and to ameliorate autoimmune disease pathology without inhibiting other pathways mediated by JAK-1, JAK-2, and Tyk-2.Methods. JAK-3 kinase selective compounds were characterized by kinase assay and JAK-3-dependent (interleukin-2 [IL-2]) and -independent (IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF]) cell-based assays measuring proliferation or STAT phosphorylation. In vivo, off-target signaling was measured by IL-22-and erythropoietin (EPO)-mediated models, while on-target signaling was measured by IL-2-mediated signaling. Efficacy of JAK-3 inhibitors was determined using delayed-type hypersensitivity (DTH) and collagen-induced arthritis (CIA) models in mice.Results. In vitro, WYE-151650 potently suppressed IL-2-induced STAT-5 phosphorylation and cell proliferation, while exhibiting 10-29-fold less activity against JAK-3-independent IL-6-or GM-CSF-induced STAT phosphorylation. Ex vivo, WYE-151650 suppressed IL-2-induced STAT phosphorylation, but not IL-6-induced STAT phosphorylation, as measured in whole blood. In vivo, WYE-151650 inhibited JAK-3-mediated IL-2-induced interferon-␥ production and decreased the natural killer cell population in mice, while not affecting IL-22-induced serum amyloid A production or EPO-induced reticulocytosis. WYE-151650 was efficacious in mouse DTH and CIA models.Conclusion. In vitro, ex vivo, and in vivo assays demonstrate that WYE-151650 is efficacious in mouse CIA despite JAK-3 selectivity. These data question the need to broadly inhibit JAK-1-, JAK-2-, or Tyk-2-dependent cytokine pathways for efficacy.

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IL-22 Increases the Innate Immunity of Tissues

Cited by 1,202 publications

References 33 publications

Distinct regulation of interleukin‐17 in human T helper lymphocytes

Distinct regulation of interleukin‐17 in human T helper lymphocytes

Pathophysiology of psoriasis: Recent advances on IL-23 and Th17 cytokines

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

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