INTERFERON INDUCTION OF TAP1 - THE PHOSPHATASE SHP-1 REGULATES CROSSOVER BETWEEN THE IFN-ALPHA BETA AND THE IFN-GAMMA SIGNAL-TRANSDUCTION PATHWAYS/

Interferon (IFN)-gamma and IFN-alpha/beta induction of the transporter associated with antigen processing-1 (TAP1) promoter was compared in HeLa cells and endothelial cells (ECs). In HeLa cells, IFN-gamma acts through Stat1 alpha/Stat1 alpha homodimers binding to the gamma activa ting sequence (GAS) and IFN-alpha/beta acts through Statl/Stat2/p48 bi nding to the IFN-stimulated response element (ISRE). In ECs, however, IFN-gamma and IFN-alpha/beta act through both the GAS and ISRE. The ba sis of the IFN signaling crossover in ECs was investigated. HeLa and E Cs contain similar ratios of Stat1 alpha to Stat2 proteins, and IFN-al pha/beta also activates the same Janus kinases (JAKs) (Jak1 and tyrosi ne kinase (Tyk) 2 but not Jak2). However, IFN-alpha/beta activates mor e Stat1 alpha. than does IFN-gamma in ECs, whereas the reverse occurs in HeLa, and expression of the IFN-alpha/beta receptor-associated phos phatase SHP-1 is much lower in ECs than HeLa cells. Overexpression of SHP-1 in ECs blocks IFN-alpha/beta signaling through GAS, and expressi on of a dominant negative SHP-1 in HeLa cells permits IFN-alpha/beta s ignaling through GAS, demonstrating a role for SHP-1 in regulating cro ssovers between the IFN-alpha/beta and IFN-gamma signaling pathways.