We show that components of the extracellular matrix (ECM) are capable of enhancing the IFN-induced activation of the FcRI gene. Various cell-binding portions of the fibronectin molecule have been analyzed, and all show an ability to enhance the response of monocytes to IFN by about 10 fold. This ability to enhance the effects of IFN at the level of gene transcription are due to the directed hyperphosphorylation of the JAK1 and JAK2 kinases, which in turn hyperphosphorylate the p91 transcription activator (stat1). The binding of fibronectin (or its cell-binding components) to the b1 integrin induces the sequence of events which results in the augmentation of the IFNg-induced signal. The work described in this report is directed at understanding how a group of cytokines activate cells of the hematopoietic lineage. An understanding of the mechanism whereby a cytokine activates a gene or transduces a signal across the cell membrane provides the scientific basis with which to conduct a more rational and comprehensive review of that cytokine prior to and during its use in clinical trials. Furthermore, we have shown how the stimulatory effects of interferon gamma can be regulated by immune complexes, and now, fibronectin. This knowledge serves to increase our understanding of how cells of the immune system respond to an environment rich in a diverse array of inflammatory stimuli. The information gained can help explain the various toxicities observed and/or the apparent lack of a clinical effect when cytokines such as interferon have been used in a variety of disease states.
