Herein we report the generation of mice lacking the ubiquitously expressed Janus kinase, Jak1. Jak1-/- mice are runted at birth, fail to nurse, and die perinatally. Although Jak1-/- cells are responsive to many cytokines, they fail to manifest biologic responses to cytokines that bind to three distinct families of cytokine receptors. These include all class II cytokine receptors, cytokine receptors that utilize the gamma(c) subunit for signaling, and the family of cytokine receptors that depend on the gp130 subunit for signaling. Our results thus demonstrate that Jak1 plays an essential and nonredundant role in promoting biologic responses induced by a select subset of cytokine receptors, including those in which Jak utilization was thought to be nonspecific.

Heart failure continues to be a leading cause of mortality worldwide. A hallmark of this disease is dilated cardiac hypertrophy, which is accompanied by a reactivation of genes expressed in fetal heart development.

Hepatocyte growth factor (HGF) is a potent mitogen, motogen, and morphogen for various epithelial cell types. The pleiotropic effects of HGF are mediated by its binding to a specific high affinity receptor, c-Met. In addition, HGF binds to heparan sulfate proteoglycans on cell surfaces and within the extracellular matrix. Incubation of HGF with 0.1, 1.0, and 10 micrograms/ml of heparin, heparan sulfate, or dextran sulfate resulted in a concentration-dependent increase in mitogenic potency in a primary rat hepatocyte bioassay, whereas sodium sulfate or fucoidan did not. Although co-incubation of HGF with sulfated compounds that enhanced HGF-dependent mitogenesis did not alter the binding isotherm of HGF for the c-Met receptor in a solid phase assay, an increase in autophosphorylation of the c-Met receptor in intact A549 cells was observed upon their addition. A series of chemically sulfated malto-oligosaccharides varying in unit size and charge was tested in the bioassay in order to provide additional insights into the nature of the HGF-heparin interaction. While sulfated di-, tri-, tetra-, and pentasaccharides did not significantly potentiate HGF-dependent mitogenesis, larger oligosaccharides such as the sulfated hexa-, hepta-, or a sulfated oligosaccharide mixture containing decasaccharides resulted in an approximate 2-, 4-, and 7-fold enhancement, respectively. We observed a correlation between the sulfated oligosaccharide preparations that enhanced mitogenic potency and those that promoted HGF oligomerization in vitro, as measured by gel filtration and analytical ultracentrifugation. These findings indicate that heparin-like molecules can stabilize HGF oligomers, which may facilitate c-Met receptor dimerization and activation.

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Several prostaglandins [prostaglandin (PG) A2, -B2, -D2, -E2, -F2 alpha, and -I2 and carbaprostacyclin] and the thromboxane analogue U-46619 were analyzed for the ability to induce hypertrophy of rat neonatal cardiac ventricular myocytes. Myocyte hypertrophy was induced specifically by PGF2 alpha. Myocytes exposed to this prostanoid in culture increased in size and protein content. The contractile fibrils within the cells became organized into parallel arrays, and the cells tended to cluster and beat spontaneously. PGF2 alpha also induced the expression of c-fos, atrial natriuretic factor (ANF), and alpha-skeletal actin in these cells. The effects of PGF2 alpha were compared with several known cardiac myocyte hypertrophy factors (phenylephrine, endothelin-1, leukemia inhibitory factor, cardiotrophin-1, and angiotensin II). PGF2 alpha was found to be intermediate in potency among the factors but induced a level of ANF production that was approximately 10-fold higher than any of the other effectors. Responsiveness to PGF2 alpha was not limited to neonatal cardiocytes. Ventricular myocytes isolated from adult rats also responded specifically to PGF2 alpha with a morphological change similar to that observed with phenylephrine and by producing ANF. In rats, chronic administration of fluprostenol, a potent agonist analogue of PGF2 alpha, resulted in a dose-dependent increase in heart weight- and ventricular weight-to-body weight ratios. The amount of PGF2 alpha extractable from the hearts of rats with cardiac hypertrophy induced by myocardial infarction was also found to be greater than that in sham-operated control rats. These results indicate that PGF2 alpha may play an important role in inducing cardiac hypertrophy.