Expression of Janus Kinase 3 in Human Endothelial and Other Non-lymphoid and Non-myeloid Cells

Verbsky, James; Bach, Erika A.; Fang, Yifu; Yang, Liping; Randolph, David A.; Fields, Larry E.

doi:10.1074/jbc.271.24.13976

Cited by 68 publications

(41 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…JAK-3 is predominantly expressed in cells of the immune system (6). Expression has been reported in other cell types on rare occasions (7,8); however, the functional significance of this is not fully understood at present. JAK-3-knockout mice have defects in T lymphocytes, B lymphocytes, and natural killer (NK) cells, with no other defects reported (9)(10)(11), and mutations in JAK-3 have been identified as a cause of autosomal-recessive severe combined immunodeficiency disorder (12,13).…”

mentioning

confidence: 99%

The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double‐blind, placebo‐controlled phase IIa trial of three dosage levels of CP‐690,550 versus placebo

Kremer

Bloom

Breedveld

et al. 2009

Arthritis & Rheumatism

506

230

View full text Add to dashboard Cite

Objective. To determine the efficacy, safety, and tolerability of 3 different dosages of CP-690,550, a potent, orally active JAK inhibitor, in patients with active rheumatoid arthritis (RA) in whom methotrexate, etanercept, infliximab, or adalimumab caused an inadequate or toxic response.Methods. Patients (n ‫؍‬ 264) were randomized equally to receive placebo, 5 mg of CP-690,550, 15 mg of CP-690,550, or 30 mg of CP-690,550 twice daily for 6 weeks, and were followed up for an additional 6 weeks after treatment. The primary efficacy end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at 6 weeks.Results. By week 6, the ACR20 response rates were 70.5%, 81.2%, and 76.8% in the 5 mg, 15 mg, and 30 mg twice daily groups, respectively, compared with 29.2% in the placebo group (P < 0.001). Improvements in disease activity in CP-690,550-treated patients compared with placebo were seen in all treatment groups as early as week 1. ACR50 and ACR70 response rates significantly improved in all treatment groups by week 4. The most common adverse events reported were headache and nausea. The infection rate in both the 15 mg twice daily group and the 30 mg twice daily group was 30.4% (versus 26.2% in the placebo group). No opportunistic infections or deaths occurred. Increases in mean low-density lipoprotein cholesterol and highdensity lipoprotein cholesterol levels, and increases in mean serum creatinine level (0.04-0.06 mg/dl) were seen in all CP-690,550 treatment arms.Conclusion. Our findings indicate that CP-690,550 is efficacious in the treatment of RA, resulting in rapid, statistically significant, and clinically meaningful reductions in the signs and symptoms of RA. Further studies of CP-690,550 in RA are warranted.ClinicalTrials.gov identifier: NCT00147498.

show abstract

mentioning

confidence: 99%

The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double‐blind, placebo‐controlled phase IIa trial of three dosage levels of CP‐690,550 versus placebo

Kremer

Bloom

Breedveld

et al. 2009

Arthritis & Rheumatism

506

230

View full text Add to dashboard Cite

show abstract

“…JAK3 is expressed constitutively at high levels in hematopoietic cells; however, it was reported that it also is expressed in human endothelial cells, including HMEC-1 (25,26). The role of JAK3 in endothelial cells is not fully understood; however, it was shown that JAK3 can contribute to interleukin-4-induced up-regulation of vascular cell adhesion molecule-1 expression, leading to the recruitment of lymphocytes and eosinophils (26).…”

Section: Discussionmentioning

confidence: 99%

Interplay between Epidermal Growth Factor Receptor and Janus Kinase 3 Regulates Polychlorinated Biphenyl–Induced Matrix Metalloproteinase-3 Expression and Transendothelial Migration of Tumor Cells

Eum

Lee

Hennig

et al. 2006

Molecular Cancer Research

View full text Add to dashboard Cite

We hypothesize that environmental toxicants, such as polychlorinated biphenyl congeners, can activate vascular endothelial cells and thus increase formation of blood-borne metastases. This study indicates that exposure of human microvascular endothelial cells to 2,2 ¶,4,6,6 ¶-pentachlorobiphenyl can stimulate transendothelial migration of tumor cells through up-regulation of matrix metalloproteinase (MMP)-3. In a series of experiments with specific small interfering RNA and pharmacologic inhibitors, we provide evidence that 2,2 ¶,4,6,6 ¶-pentachlorobiphenyl can activate epidermal growth factor receptor (EGFR) and Janus kinase 3 (JAK3) in a closely coordinated and cross-dependent fashion. Activated EGFR and JAK3 stimulate in concert c-Jun NH 2 -terminal kinase and extracellular signal-regulated kinase 1/2 as well as increase DNA-binding activity of transcription factors activator protein-1 and polyomavirus enhancer activator protein 3, leading to transcriptional up-regulation of MMP-3 expression. These results indicate that the interplay among EGFR, JAK3, and mitogen-activated protein kinases, such as c-Jun NH 2 -terminal kinase and extracellular signal-regulated kinase 1/2, is critical for polychlorinated biphenyl -induced MMP-3 expression and accelerated transendothelial migration of tumor cells. (Mol Cancer Res 2006;4(6):361 -70)

show abstract

“…These two studies analyzed resting, unstimulated endothelial cells that express little Jak3. Our own data had shown that endothelial cells must be activated before Jak3 can be readily detected (28), indicating that the functional repertoire of this signaling molecule cannot be inferred from its expression pattern in resting cells.…”

Section: Nonhematopoietic Expression Of Janus Kinase 3 Is Required Fomentioning

confidence: 99%

Nonhematopoietic Expression of Janus Kinase 3 Is Required for Efficient Recruitment of Th2 Lymphocytes and Eosinophils in OVA-Induced Airway Inflammation

Verbsky

Randolph

Shornick

et al. 2002

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Tyrosine kinases of the Janus kinase (Jak) family transduce signals from the type I and type II cytokine receptors. Jak3 is unique in this family because its expression must be induced and is predominantly limited to cells of the lymphoid and myeloid lineages. Deficient expression of Jak3 interferes with normal development and function of T, B, and NK cells. Using irradiated Jak3-deficient (Jak3−/−) mice reconstituted with normal bone marrow (Jak3−/− chimeric mice), we have investigated possible actions of Jak3 outside of the hematopoietic system. We show that efficient recruitment of inflammatory cells to the airways of OVA-sensitized mice challenged with aerosolized OVA requires the expression of Jak3 in radioresistant nonhematopoietic cells. Failure to develop eosinophil-predominant airway inflammation in Jak3−/− chimeric mice is not due to failure of T cell sensitization, because Jak3−/− chimeric mice showed delayed-type hypersensitivity responses indistinguishable from wild-type chimeric mice. Jak3−/− chimeric mice, however, express less endothelial-associated VCAM-1 after airway Ag challenge. Given the key role of VCAM-1 in recruitment of Th2 cells and eosinophils, our data suggest that Jak3 in airway-associated endothelial cells is required for the expression of eosinophilic airway inflammation. This requirement for nonhematopoietic expression of Jak3 represents the first demonstration of a physiological function of Jak3 outside of the lymphoid lineages.

show abstract

Expression of Janus Kinase 3 in Human Endothelial and Other Non-lymphoid and Non-myeloid Cells

Cited by 68 publications

References 27 publications

The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double‐blind, placebo‐controlled phase IIa trial of three dosage levels of CP‐690,550 versus placebo

The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double‐blind, placebo‐controlled phase IIa trial of three dosage levels of CP‐690,550 versus placebo

Interplay between Epidermal Growth Factor Receptor and Janus Kinase 3 Regulates Polychlorinated Biphenyl–Induced Matrix Metalloproteinase-3 Expression and Transendothelial Migration of Tumor Cells

Nonhematopoietic Expression of Janus Kinase 3 Is Required for Efficient Recruitment of Th2 Lymphocytes and Eosinophils in OVA-Induced Airway Inflammation

Contact Info

Product

Resources

About