L-selectin gene expression is regulated by an interferon-α responsive signal transduction pathway

The leukocyte adhesion molecule L-selectin plays a crucial role in directing lymphocyte trafficking to peripheral tissues, a process fundamental to mammalian immune responses. We have recently shown that L-selectin transcription is induced by interferon-α (IFN-α) in IFN-sensitive but not resistant human lymphoblastoid cell lines by a signaling pathway that involves activation of pre-existing cellular factors and tyrosine kinase activity, hallmarks of the pathway utilized by IFN-α to activate classical IFN-stimulated genes (ISGs). IFN-α induction of ISGs is dependent on the JAK (Janus kinase) family of tyrosine kinases and on STAT (signal transducers and activators of transcription) proteins. The present study was undertaken to identify defect(s) in the JAK/STAT pathway in the IFN-resistant cell line in order to gain insight into the nature of the factors which regulate L-selectin gene expression. IFN-resistant cells were found to express abnormally low levels of STAT1 and STAT2 proteins, two critical components of the transcription factor termed ISGF3 which controls classical ISG expression. In contrast, the IFN-resistant subclone is not deficient with respect to the expression of another ISGF3 component, p48, or of JAKl and TYK2, two important JAK-family tyrosine kinases which control transcription of IFN-stimulated genes. These data strongly implicate the STAT1 and STAT2 signal transduction molecules in playing a central role in the regulation of L-selectin gene expression and provide insight into the nature of the cytokine cascade which controls L selectin synthesis.