Erythropoietin-producing hepatocellular (
Eph) receptor tyrosine kinases and their
ligands,
ephrins, are involved in embryogenesis and
oncogenesis by mediating cell adhesion and migration. Although
ephrins can be induced by bacterial LPS in vitro, whether they are involved in
inflammation in vivo is unknown. Using differential
mRNA display, we found that a febrigenic dose of LPS (50 microg/kg iv) induces a strong transcriptional upregulation of
ephrin-A1 in rat liver. We confirmed this finding by real-time RT-PCR. We then quantified the
mRNA expression of different
ephrins and
Eph receptors at phases 1-3 of LPS
fever in different organs. Febrile phases 2 (90 min post-LPS) and 3 (300 min) were characterized by robust upregulation (up to 16-fold) and downregulation (up to 21-fold) of several
ephrins and
Eph receptors. With the exception of EphA2, which showed upregulation in the brain at phase 2, expressional changes of
Eph receptors and
ephrins were limited to the LPS-processing organs: liver and lung. Characteristic, counter-directed changes in expressional regulation of
Eph receptors and their corresponding
ligands were found: upregulation of EphA2, downregulation of
ephrin-A1 in the liver and lung at phase 2; downregulation of EphB3, upregulation of
ephrin-B2 in the liver at phase 2; downregulation of EphA1 and EphA3, upregulation of ephrins-A1 and -A3 in liver at phase 3. In the liver, transcriptional changes of EphA2 and EphB3 at phase 2 were confirmed at
protein level. These coordinated, phase-specific responses suggest that different sets of
ephrins and
Eph receptors may be involved in cellular events (such as disruption of tissue barriers and leukocyte transmigration) underlying different stages of systemic inflammatory response to LPS.