Novak, Thomas J. and Chen, Dan and Rothenberg, Ellen V. (1990) Interleukin-1 Synergy with Phosphoinositide Pathway Agonists for Induction of Interleukin-2 Gene Expression: Molecular Basis of Costimulation. Molecular and Cellular Biology, 10 (12). pp. 6325-6334. ISSN 0270-7306. http://resolver.caltech.edu/CaltechAUTHORS:NOVmcb90
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The macrophage-derived cytokine interleukin-1 (IL-1) can provide a second signal with antigen to elicit production of interleukin-2 (IL-2) by helper T cells. The pathway(s) involved remains controversial, with protein kinase C and cyclic AMP (cAMP) invoked as possible second messengers. In the murine thymoma EL4.E1, IL-1 could synergize with the phosphoinositide pathway, because the cells made higher levels of IL-2 in the presence of IL-1 than could be induced by phorbol ester plus calcium ionophore alone. IL-1 is unlikely to act through a sustained increase in cAMP in these cells because it did not raise cAMP levels detectably and because IL-1 and forskolin had opposite effects on IL-2 gene expression. Inducible expression of a transfected reporter gene linked to a cloned fragment of the murine IL-2 gene promoter was initially increased by IL-1 costimulation, implying that IL-1 can increase the rate of transcription of IL-2. The minimal promoter elements required for IL-1 responsiveness were located within 321 bp of the IL-2 RNA cap site, and further upstream sequences to -2800 did not modify this response. IL-1 costimulation resulted in enhanced activity of both an inducible NF-KB-like factor and one of two distinct AP-1-like factors that bind to IL-2 regulatory sequences. Neither was induced, however, by IL-1 alone. Another AP-1-like factor and NFAT-1, while inducible in other cel types, were expressed constitutively in the EL4.E1 cells and were unaffected by IL-1. These results are discussed in terms of the combinatorial logic of IL-2 gene expression.
|Additional Information:||Copyright © 1990, American Society for Microbiology. Reprinted with permission. Received 4 June 1990/Accepted 24 August 1990 We thank Jerry Crabtree for his generous provision of cells, protocols, and advice, Frank Calzone and Eric Davidson for their critical guidance and encouragement, Cherrie Leighton for excellent graphics, and Cathy Blagg and Renee Thorf for careful preparation of the manuscript. Support for this work was provided by the Lucille P. Markey Charitable Trust and by Public Health Service grant CA 39605 from the National Cancer Institute to E.V.R. T.J.N. was supported in part by a predoctoral training grant from the Public Health Service, and D.C. gratefully acknowledges support from a Gordon Ross Medical Fellowship.|
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