Selective functional inhibition of JAK-3 is sufficient for efficacy in collagen-induced arthritis in mice - PubMed (original) (raw)

. 2010 Aug;62(8):2283-93.

doi: 10.1002/art.27536.

Martin Hegen, Elizabeth Quadros, Cheryl L Nickerson-Nutter, Kenneth C Appell, Andrew G Cole, Yuefei Shao, Steve Tam, Michael Ohlmeyer, Bojing Wang, Debra G Goodwin, Earl F Kimble, Jorge Quintero, Min Gao, Peter Symanowicz, Christopher Wrocklage, Jennifer Lussier, Scott H Schelling, Amha G Hewet, Dejun Xuan, Rustem Krykbaev, Jenny Togias, Xin Xu, Richard Harrison, Tarek Mansour, Mary Collins, James D Clark, Maria L Webb, Katherine J Seidl

Affiliations

Free article

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

Tsung H Lin et al. Arthritis Rheum. 2010 Aug.

Free article

Abstract

Objective: All gamma-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-gamma 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.

PubMed Disclaimer

Similar articles

Cited by

Publication types

MeSH terms

Substances

LinkOut - more resources