Although it is known that cytokines trigger rapid tyrosine phosphorylation of a common set of cellular proteins as well as induction of several of the same early response genes, the mechanisms by which these genes are activated is not well understood. We have previously shown that the interferons, GM-CSF, IL-6, LIF and OSM stimulate the assembly of protein complexes which recognize conserved sequences within the enhancers of two genes (IRF-1 and FcgRI) that are rapidly activated by these cytokines. These enhancers are known to be required for transcriptional induction of these genes by IFNg. Assembly of the DNA-binding protein complexes occurs within minutes after ligand addition and depends upon tyrosine phosphorylation. These complexes contain the stat transcription factors, which are tyrosine phosphorylated in response to these cytokines. Thus, many cytokines and the interferons activate stat1, whereas GM-CSF induces the phosphorylation of stat5. We have shown that components of the extracellular matrix (ECM) are capable of enhancing the IFN-induced expression of the FcgRI gene. Exploring the mechanism whereby FcgRI expression was enhanced in this model system, we found that exposure of monocytes to cell-binding components of fibronectin for as little as 15 minutes was sufficient to enhance the IFN-induced level of phosphorylation of the kinases JAK1, JAK2, and and of the DNA binding protein p91, suggesting that the mechanism whereby the ECM enhances the IFN-induced response is through the directed stimulation of the IFN signalling pathway which is comprised of JAK1, JAK2 and p91. Further studies have delineated the role of the b1 integrin subunit of the fibronectin receptor as the signalling molecule responsible for this augmentation of the IFNg response.
