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

Abstract

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.

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

“…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).…”

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

“…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). The expression levels of JAK3 in endothelial cells were also shown to be significantly increased by stimulation with interleukin-1h, tumor necrosis factor-a, and lipopolysaccharide (25).…”

Novel Immunosuppression: R348, a JAK3- and Syk-Inhibitor Attenuates Acute Cardiac Allograft Rejection

“…JAK3 inhibition might provoke immunosuppression by selectively altering the expression, function, and interaction of immune cells. Although nonhematopoietic expression of JAK3 has been demonstrated, its functional relevance remains to be determined (9). This is the first report on the novel JAK3 inhibitor R348.…”