Selective functional inhibition of JAK-3 is sufficient for efficacy in collagen-induced arthritis in mice
Version of Record online: 29 APR 2010
Copyright © 2010 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 62, Issue 8, pages 2283–2293, August 2010
How to Cite
Lin, T. H., Hegen, M., Quadros, E., Nickerson-Nutter, C. L., Appell, K. C., Cole, A. G., Shao, Y., Tam, S., Ohlmeyer, M., Wang, B., Goodwin, D. G., Kimble, E. F., Quintero, J., Gao, M., Symanowicz, P., Wrocklage, C., Lussier, J., Schelling, S. H., Hewet, A. G., Xuan, D., Krykbaev, R., Togias, J., Xu, X., Harrison, R., Mansour, T., Collins, M., Clark, J. D., Webb, M. L. and Seidl, K. J. (2010), Selective functional inhibition of JAK-3 is sufficient for efficacy in collagen-induced arthritis in mice. Arthritis & Rheumatism, 62: 2283–2293. doi: 10.1002/art.27536
- Issue online: 3 AUG 2010
- Version of Record online: 29 APR 2010
- Manuscript Accepted: 20 APR 2010
- Manuscript Received: 3 DEC 2009
- Wyeth Research, now a fully owned subsidiary of Pfizer
All γ-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.
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.
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-γ 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.
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.