|Budget Amount *help
¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2001: ¥2,700,000 (Direct Cost: ¥2,700,000)
Cross talk between distinct receptor components is often important to amplify, suppress or modulate a given receptor signalling pathway by the other, and this is an aspect critical to generate diversity of cellular responses. In this study, we sought to explore a novel regulatory mechanism(s) in cytokine signal transduction, particularly in terms of the possible involvement of membrane domains in signalling efficiency, specificity and cross talk among cytokine signallings. In this context, we previously reported on the critical role of the IFN-α/β signalling complex, generated by constitutively produced IFN-α/(3, in IFN-γ signalling. As a result of the extended study, here, we found a novel cross talk between interferon (IFN)-α/β and interleukin (IL)-6 signallings, wherein the constitutive, weak IFN-α/β signalling also contributes to enhance the IL-6 signalling. The previous and present studies showed that the receptor components for IFN-α/β, IFN-γ, and IL-6 were concentrated in caveol
ar membrane fractions, i.e., membrane domains. This suggests that these receptor components seem to be in close proximity to forma mulli-subunit complex, which may be termed "receptosome", so as to make efficient signalling for these cytokines. In addition, these results show a possibility that these membrane domains play a role as a signalling scaffold for these receptor components during the cytokine signalling.
Through these series of studies, we demonstrated a unique facet of a weak signalling by IFN-α/β, which is constitutively produced at a low level in the absence of viral infection. In fact, we additionally found that this weak signal also contributes to amplification of IFN-α/β production in response to viral infection. Therefore, this weak signalling, described in the context of what we propose as a "revving-up system", was found to provide a foundation for a more efficient and robust signalling in host defense.
We also showed the possible role of the constitutive, weak IFN-α/β signalling in suppression of oncogenesis, in terms of a unique tumor urveillance system. Furthermore, we found a novel inter-relationship between IFN-α/β signalling and p53 response in tumor suppression, which may provide a possible underlying mechanism to the direct effect of IFN in tumor suppression.
Taken together, we believe that these research accomplishments made progress in the study on the elucidation of advanced complex mechanisms for the regulation of cellular signalling events, and that further extended studies will provide any contributions not only to the elucidation of underlying signalling aspects which cause cancer or autoimmune diseases, but to their therapeutic applications Less