Interleukin-1-mediated Stabilization of Mouse KC mRNA Depends on Sequences in both 5′- and 3′-Untranslated Regions

Abstract

mRNA transcribed from the mouse KC chemokine gene accumulated to significantly higher levels in multiple cell types after treatment with interleukin 1α (IL-1α) as compared with tumor necrosis factor-α (TNFα). Although TNFα and IL-1α both signaled the activation of nuclear factor κB and enhanced transcription of the KC gene with equal potency, only IL-1α treatment resulted in stabilization of KC mRNA. Nucleotide sequences that confer sensitivity for IL-1α-mediated mRNA stabilization were identified within the 5′- and 3′-untranslated regions (UTRs) of KC mRNA using transient transfection of chimeric plasmids containing specific portions of KC mRNA linked to the chloramphenicol acetyltransferase (CAT) gene. When plasmids containing either the 3′- or 5′-UTR of KC mRNA were used, the half-life of CAT mRNA was unaltered either in untreated or IL-1α-stimulated cells. In contrast, CAT mRNA transcribed from plasmids that contained both the 5′- and 3′-UTRs of the KC mRNA decayed more rapidly than control CAT mRNA, and this enhanced decay was prevented in cells treated with IL-1α. A cluster of four overlapping AUUUA motifs within the 3′-UTR was required, whereas the 5′-UTR region exhibited orientation dependence. These findings indicate that cooperative function of the two nucleotide sequences involves a distinct signaling pathway used by IL-1α but not TNFα. mRNA transcribed from the mouse KC chemokine gene accumulated to significantly higher levels in multiple cell types after treatment with interleukin 1α (IL-1α) as compared with tumor necrosis factor-α (TNFα). Although TNFα and IL-1α both signaled the activation of nuclear factor κB and enhanced transcription of the KC gene with equal potency, only IL-1α treatment resulted in stabilization of KC mRNA. Nucleotide sequences that confer sensitivity for IL-1α-mediated mRNA stabilization were identified within the 5′- and 3′-untranslated regions (UTRs) of KC mRNA using transient transfection of chimeric plasmids containing specific portions of KC mRNA linked to the chloramphenicol acetyltransferase (CAT) gene. When plasmids containing either the 3′- or 5′-UTR of KC mRNA were used, the half-life of CAT mRNA was unaltered either in untreated or IL-1α-stimulated cells. In contrast, CAT mRNA transcribed from plasmids that contained both the 5′- and 3′-UTRs of the KC mRNA decayed more rapidly than control CAT mRNA, and this enhanced decay was prevented in cells treated with IL-1α. A cluster of four overlapping AUUUA motifs within the 3′-UTR was required, whereas the 5′-UTR region exhibited orientation dependence. These findings indicate that cooperative function of the two nucleotide sequences involves a distinct signaling pathway used by IL-1α but not TNFα. interleukin tumor necrosis factor nuclear factor κB chloramphenicol acetyltransferase actinomycin D ribonuclease protection assay nucleotide(s) AU-rich sequence element The development of an inflammatory response is mediated, in part, by the modulation of gene expression in multiple participating cell types (1.Adams D.O. Hamilton T.A. Gallin J.I. Goldstein I.M. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. Raven Press, Ltd., New York1992: 637-662Google Scholar, 2.Ohmori Y. Hamilton T.A. Pharmacol. Ther. 1994; 63: 235-264Crossref PubMed Scopus (39) Google Scholar, 3.Nathan C.F. Cohn Z.A. Kelly W. Harris E. Ruddy S. Hedge R. Textbook of Rheumatology. W. B. Saunders Co., New York1995: 144-169Google Scholar, 4.Miyajima A. Miyatake S. Schreurs J. De Vries J. Arai N. Yokota T. Arai K. FASEB J. 1988; 2: 2462-2473Crossref PubMed Scopus (135) Google Scholar). The changes in gene expression associated with inflammation are stringently controlled in response to extracellular signals encountered in the microenvironment of the inflammatory site. Among the most potent of such signals are the cytokines interleukin-1α/β (IL-1α/β)1 and tumor necrosis factor-α (TNFα). Although IL-1α and TNFα are structurally unrelated and interact with distinct receptors, they induce a very similar set of functional responses in many cell types (5.Vilcek J. Lee T.H. J. Biol. Chem. 1991; 266: 7313-7316Abstract Full Text PDF PubMed Google Scholar, 6.Le J. Vilcek J. Lab. Invest. 1987; 56: 234-248PubMed Google Scholar, 7.Dinarello C.A. Eur. Cytokine. Netw. 1994; 5: 517-531PubMed Google Scholar, 8.Beutler B. J. Invest. Med. 1995; 43: 227-235PubMed Google Scholar). Indeed, some components of the intracellular signaling pathways that mediate cellular response to TNFα and IL-1α are shared (9.Malinin N.L. Boldin M.P. Kovalenko A.V. Wallach D. Nature. 1997; 385: 540-544Crossref PubMed Scopus (1159) Google Scholar, 10.Wallach D. Varfolomeev E.E. Malinin N.L. Goltsev Y.V. Kovalenko A.V. Boldin M.P. Annu. Rev. Immunol. 1999; 17: 331-367Crossref PubMed Scopus (1121) Google Scholar, 11.Jobin C. Holt L. Bradham C.A. Streetz K. Brenner D.A. Sartor R.B. J. Immunol. 1999; 162: 4447-4454PubMed Google Scholar, 12.Auron P.E. Cytokine Growth Factor Rev. 1998; 9: 221-237Crossref PubMed Scopus (154) Google Scholar, 13.O'Neill L.A. Greene C. J. Leukocyte Biol. 1998; 63: 650-657Crossref PubMed Scopus (494) Google Scholar). These signaling pathways lead to alterations in gene transcription, in mRNA stability, and in mRNA translation (10.Wallach D. Varfolomeev E.E. Malinin N.L. Goltsev Y.V. Kovalenko A.V. Boldin M.P. Annu. Rev. Immunol. 1999; 17: 331-367Crossref PubMed Scopus (1121) Google Scholar,13.O'Neill L.A. Greene C. J. Leukocyte Biol. 1998; 63: 650-657Crossref PubMed Scopus (494) Google Scholar, 14.Eder J. Trends Pharmacol. Sci. 1997; 18: 319-322Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, Biol. 1999; PubMed Scopus Google Scholar, J. J. A. 1999; Google of the or chemokine gene are as of inflammation N. J. Med. 1998; PubMed Scopus Google Scholar, Nature. 1998; PubMed Scopus Google Scholar, 1997; PubMed Google Scholar). The of to of inflammatory and the and of an inflammatory In the of the in inflammation is the of a controlled in by of the chemokine that and N. J. Med. 1998; PubMed Scopus Google Scholar, Nature. 1998; PubMed Scopus Google Scholar, 1997; PubMed Google Scholar). is of in the the are KC and B. Y. A. Google Scholar, J. D. R. J. Biol. Chem. Full Text PDF PubMed Google Scholar). of the mouse KC gene is by a of inflammatory and in a of cell types and cells Biol. 9: PubMed Scopus Google Scholar, C. J. PubMed Scopus Google Scholar, Hamilton T.A. D.O. J. Immunol. 1987; Scholar, Hamilton T.A. P.E. J. PubMed Scopus Google Scholar, Hamilton T.A. P.E. 2: Scopus Google Scholar). Although KC mRNA expression KC gene transcription the of IL-1α to the of KC mRNA by half-life in cells Y. Hamilton T.A. 1994; 2: Scopus Google Scholar, Y. S. Hamilton T.A. J. Immunol. 1995; Google the the by IL-1α KC mRNA. Although TNFα and IL-1α are both for the activation of and associated changes in gene transcription, only IL-1α KC mRNA. both the of KC mRNA and the sensitivity to IL-1α two nucleotide sequences within the mRNA. Although a cluster of four overlapping AUUUA in the 3′-UTR is for both decay and IL-1α-mediated this sequence is by and the the 5′-UTR as are to in the development and of inflammatory N. J. Med. 1998; PubMed Scopus Google Scholar, Nature. 1998; PubMed Scopus Google Scholar, 1997; PubMed Google Scholar). The overlapping cell and of many that the control of chemokine an of distinct 1997; PubMed Google Scholar). The expression of many chemokine is to controlled the of transcription, and the are Y. Hamilton T.A. 1994; 2: Scopus Google Scholar, Y. S. Hamilton T.A. J. Immunol. 1995; Google Scholar, Y. L. S. D. Hamilton T.A. J. Google Scholar, Y. Hamilton T.A. J. Biol. Chem. Full Text PDF PubMed Google Scholar, K. S. N. S. K. J. Biol. Chem. Full Text PDF PubMed Google Scholar, T. K. Y. N. K. T. S. Sci. S. A. PubMed Scopus Google Scholar). is that are Indeed, from this and that changes in specific chemokine mRNA an and of the of specific chemokine gene expression Y. Hamilton T.A. 1994; 2: Scopus Google Scholar, T. J. Immunol. 1994; Google Scholar, D. Hamilton T.A. J. Leukocyte Biol. 1998; PubMed Scopus Google Scholar, R. Hamilton T.A. J. Immunol. 1999; 162: Google Scholar). In the the IL-1α-mediated of mouse KC gene The of the IL-1α-mediated stabilization of KC mRNA is a that in and cell The intracellular signaling pathway to the activation of is not for alterations in KC mRNA Nucleotide sequences in the 5′-UTR and 3′-UTR of KC mRNA are both for the and for sensitivity to IL-1α for mRNA and TNFα are to overlapping functional that the to gene expression in a of cell types (5.Vilcek J. Lee T.H. J. Biol. Chem. 1991; 266: 7313-7316Abstract Full Text PDF PubMed Google Scholar, 6.Le J. Vilcek J. Lab. Invest. 1987; 56: 234-248PubMed Google Scholar, 7.Dinarello C.A. Eur. Cytokine. Netw. 1994; 5: 517-531PubMed Google Scholar, 8.Beutler B. J. Invest. Med. 1995; 43: 227-235PubMed Google Scholar). many intracellular signaling components (9.Malinin N.L. Boldin M.P. Kovalenko A.V. Wallach D. Nature. 1997; 385: 540-544Crossref PubMed Scopus (1159) Google Scholar, 10.Wallach D. Varfolomeev E.E. Malinin N.L. Goltsev Y.V. Kovalenko A.V. Boldin M.P. Annu. Rev. Immunol. 1999; 17: 331-367Crossref PubMed Scopus (1121) Google Scholar, 11.Jobin C. Holt L. Bradham C.A. Streetz K. Brenner D.A. Sartor R.B. J. Immunol. 1999; 162: 4447-4454PubMed Google Scholar, 12.Auron P.E. Cytokine Growth Factor Rev. 1998; 9: 221-237Crossref PubMed Scopus (154) Google Scholar, 13.O'Neill L.A. Greene C. J. Leukocyte Biol. 1998; 63: 650-657Crossref PubMed Scopus (494) Google Scholar). both TNFα and are to the activation of and the both were for the of the activation of κB and the of gene by either IL-1α or TNFα to a of that are distinct for (10.Wallach D. Varfolomeev E.E. Malinin N.L. Goltsev Y.V. Kovalenko A.V. Boldin M.P. Annu. Rev. Immunol. 1999; 17: 331-367Crossref PubMed Scopus (1121) Google Scholar, 12.Auron P.E. Cytokine Growth Factor Rev. 1998; 9: 221-237Crossref PubMed Scopus (154) Google Scholar, 13.O'Neill L.A. Greene C. J. Leukocyte Biol. 1998; 63: 650-657Crossref PubMed Scopus (494) Google Scholar). with of and in the components the and the and nuclear of The that IL-1α but not TNFα the stabilization of KC mRNA that IL-1α is to signaling that are not shared with TNFα. In this TNFα and to in some cell types to signaling pathways to the J. Trends Pharmacol. Sci. 1997; 18: 319-322Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, J. J. A. 1999; Google Scholar, S. A. J. Med. 1998; PubMed Scopus Google Scholar). a of this is to the of the signaling pathways J. Trends Pharmacol. Sci. 1997; 18: 319-322Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, J. J. A. 1999; Google Scholar, S. A. J. Med. 1998; PubMed Scopus Google and signaling pathways with of mRNA 1998; PubMed Scopus Google Scholar, J. 1998; PubMed Scopus Google that the of specific and 1991; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, L. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). is specific sequences in the is for sequences in that control transcription, multiple in a mRNA that either or the half-life of the 1998; PubMed Scopus Google Scholar, L. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). regions in both the 5′-UTR and the 3′-UTR of function in cooperative to confer sensitivity to 1998; PubMed Scopus Google Scholar, L. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). The findings and more of the of the sequence regions that are Although both the 5′-UTR and a of the 3′-UTR containing an cluster are required, the of the mRNA only both sequences are is the mRNA and to IL-1α-mediated are by distinct or function as of a to is that the sequence in the KC 3′-UTR that is for and IL-1α sensitivity a AU-rich of four overlapping AUUUA sequence motifs are to of the of many factor and J. Rev. 1995; Google Scholar, Trends Sci. 1995; Full Text PDF PubMed Scopus Google Scholar, D. B. K. R. S. A. Sci. S. A. PubMed Scopus Google Scholar, R. Full Text PDF PubMed Scopus Google Scholar). of the mRNA that of the mRNA the in an mRNA for and this is in part, by the of the N. Biol. 1997; 17: PubMed Scopus Google Scholar). sensitivity for modulation of is a of or is to a is not many that sequence for E. D. Biol. PubMed Scopus Google Scholar, W. K. De D. De K. L. Biol. PubMed Scopus Google Scholar, J. 1997; PubMed Scopus Google Scholar, D. J. 1997; Full Text PDF PubMed Scopus Google Scholar, Biol. 1999; PubMed Scopus Google Scholar). two of The four of or is and to and the of J. 1998; 17: PubMed Scopus Google Scholar, N. J. 1998; 17: PubMed Scopus Google Scholar, J. J. 1999; PubMed Scopus Google Scholar). A is and is a of the nuclear Y. 1998; PubMed Scopus Google Scholar). The of the with an containing mRNA is with mRNA with to the mRNA J. 1998; 17: PubMed Scopus Google Scholar, N. J. 1998; 17: PubMed Scopus Google Scholar, J. J. 1999; PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, 1999; PubMed Scopus Google Scholar). of in the of IL-1α-mediated KC mRNA stabilization the of The development of an inflammatory response is mediated, in part, by the modulation of gene expression in multiple participating cell types (1.Adams D.O. Hamilton T.A. Gallin J.I. Goldstein I.M. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. Raven Press, Ltd., New York1992: 637-662Google Scholar, 2.Ohmori Y. Hamilton T.A. Pharmacol. Ther. 1994; 63: 235-264Crossref PubMed Scopus (39) Google Scholar, 3.Nathan C.F. Cohn Z.A. Kelly W. Harris E. Ruddy S. Hedge R. Textbook of Rheumatology. W. B. Saunders Co., New York1995: 144-169Google Scholar, 4.Miyajima A. Miyatake S. Schreurs J. De Vries J. Arai N. Yokota T. Arai K. FASEB J. 1988; 2: 2462-2473Crossref PubMed Scopus (135) Google Scholar). The changes in gene expression associated with inflammation are stringently controlled in response to extracellular signals encountered in the microenvironment of the inflammatory site. Among the most potent of such signals are the cytokines interleukin-1α/β (IL-1α/β)1 and tumor necrosis factor-α (TNFα). Although IL-1α and TNFα are structurally unrelated and interact with distinct receptors, they induce a very similar set of functional responses in many cell types (5.Vilcek J. Lee T.H. J. Biol. Chem. 1991; 266: 7313-7316Abstract Full Text PDF PubMed Google Scholar, 6.Le J. Vilcek J. Lab. Invest. 1987; 56: 234-248PubMed Google Scholar, 7.Dinarello C.A. Eur. Cytokine. Netw. 1994; 5: 517-531PubMed Google Scholar, 8.Beutler B. J. Invest. Med. 1995; 43: 227-235PubMed Google Scholar). Indeed, some components of the intracellular signaling pathways that mediate cellular response to TNFα and IL-1α are shared (9.Malinin N.L. Boldin M.P. Kovalenko A.V. Wallach D. Nature. 1997; 385: 540-544Crossref PubMed Scopus (1159) Google Scholar, 10.Wallach D. Varfolomeev E.E. Malinin N.L. Goltsev Y.V. Kovalenko A.V. Boldin M.P. Annu. Rev. Immunol. 1999; 17: 331-367Crossref PubMed Scopus (1121) Google Scholar, 11.Jobin C. Holt L. Bradham C.A. Streetz K. Brenner D.A. Sartor R.B. J. Immunol. 1999; 162: 4447-4454PubMed Google Scholar, 12.Auron P.E. Cytokine Growth Factor Rev. 1998; 9: 221-237Crossref PubMed Scopus (154) Google Scholar, 13.O'Neill L.A. Greene C. J. Leukocyte Biol. 1998; 63: 650-657Crossref PubMed Scopus (494) Google Scholar). These signaling pathways lead to alterations in gene transcription, in mRNA stability, and in mRNA translation (10.Wallach D. Varfolomeev E.E. Malinin N.L. Goltsev Y.V. Kovalenko A.V. Boldin M.P. Annu. Rev. Immunol. 1999; 17: 331-367Crossref PubMed Scopus (1121) Google Scholar,13.O'Neill L.A. Greene C. J. Leukocyte Biol. 1998; 63: 650-657Crossref PubMed Scopus (494) Google Scholar, 14.Eder J. Trends Pharmacol. Sci. 1997; 18: 319-322Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, Biol. 1999; PubMed Scopus Google Scholar, J. J. A. 1999; Google Scholar). of the or chemokine gene are as of inflammation N. J. Med. 1998; PubMed Scopus Google Scholar, Nature. 1998; PubMed Scopus Google Scholar, 1997; PubMed Google Scholar). The of to of inflammatory and the and of an inflammatory In the of the in inflammation is the of a controlled in by of the chemokine that and N. J. Med. 1998; PubMed Scopus Google Scholar, Nature. 1998; PubMed Scopus Google Scholar, 1997; PubMed Google Scholar). is of in the the are KC and B. Y. A. Google Scholar, J. D. R. J. Biol. Chem. Full Text PDF PubMed Google Scholar). of the mouse KC gene is by a of inflammatory and in a of cell types and cells Biol. 9: PubMed Scopus Google Scholar, C. J. PubMed Scopus Google Scholar, Hamilton T.A. D.O. J. Immunol. 1987; Scholar, Hamilton T.A. P.E. J. PubMed Scopus Google Scholar, Hamilton T.A. P.E. 2: Scopus Google Scholar). Although KC mRNA expression KC gene transcription the of IL-1α to the of KC mRNA by half-life in cells Y. Hamilton T.A. 1994; 2: Scopus Google Scholar, Y. S. Hamilton T.A. J. Immunol. 1995; Google Scholar). In the the by IL-1α KC mRNA. Although TNFα and IL-1α are both for the activation of and associated changes in gene transcription, only IL-1α KC mRNA. both the of KC mRNA and the sensitivity to IL-1α two nucleotide sequences within the mRNA. Although a cluster of four overlapping AUUUA in the 3′-UTR is for both decay and IL-1α-mediated this sequence is by and the the 5′-UTR as are to in the development and of inflammatory N. J. Med. 1998; PubMed Scopus Google Scholar, Nature. 1998; PubMed Scopus Google Scholar, 1997; PubMed Google Scholar). The overlapping cell and of many that the control of chemokine an of distinct 1997; PubMed Google Scholar). The expression of many chemokine is to controlled the of transcription, and the are Y. Hamilton T.A. 1994; 2: Scopus Google Scholar, Y. S. Hamilton T.A. J. Immunol. 1995; Google Scholar, Y. L. S. D. Hamilton T.A. J. Google Scholar, Y. Hamilton T.A. J. Biol. Chem. Full Text PDF PubMed Google Scholar, K. S. N. S. K. J. Biol. Chem. Full Text PDF PubMed Google Scholar, T. K. Y. N. K. T. S. Sci. S. A. PubMed Scopus Google Scholar). is that are Indeed, from this and that changes in specific chemokine mRNA an and of the of specific chemokine gene expression Y. Hamilton T.A. 1994; 2: Scopus Google Scholar, T. J. Immunol. 1994; Google Scholar, D. Hamilton T.A. J. Leukocyte Biol. 1998; PubMed Scopus Google Scholar, R. Hamilton T.A. J. Immunol. 1999; 162: Google Scholar). In the the IL-1α-mediated of mouse KC gene The of the IL-1α-mediated stabilization of KC mRNA is a that in and cell The intracellular signaling pathway to the activation of is not for alterations in KC mRNA Nucleotide sequences in the 5′-UTR and 3′-UTR of KC mRNA are both for the and for sensitivity to IL-1α for mRNA and TNFα are to overlapping functional that the to gene expression in a of cell types (5.Vilcek J. Lee T.H. J. Biol. Chem. 1991; 266: 7313-7316Abstract Full Text PDF PubMed Google Scholar, 6.Le J. Vilcek J. Lab. Invest. 1987; 56: 234-248PubMed Google Scholar, 7.Dinarello C.A. Eur. Cytokine. Netw. 1994; 5: 517-531PubMed Google Scholar, 8.Beutler B. J. Invest. Med. 1995; 43: 227-235PubMed Google Scholar). many intracellular signaling components (9.Malinin N.L. Boldin M.P. Kovalenko A.V. Wallach D. Nature. 1997; 385: 540-544Crossref PubMed Scopus (1159) Google Scholar, 10.Wallach D. Varfolomeev E.E. Malinin N.L. Goltsev Y.V. Kovalenko A.V. Boldin M.P. Annu. Rev. Immunol. 1999; 17: 331-367Crossref PubMed Scopus (1121) Google Scholar, 11.Jobin C. Holt L. Bradham C.A. Streetz K. Brenner D.A. Sartor R.B. J. Immunol. 1999; 162: 4447-4454PubMed Google Scholar, 12.Auron P.E. Cytokine Growth Factor Rev. 1998; 9: 221-237Crossref PubMed Scopus (154) Google Scholar, 13.O'Neill L.A. Greene C. J. Leukocyte Biol. 1998; 63: 650-657Crossref PubMed Scopus (494) Google Scholar). both TNFα and are to the activation of and the both were for the of the activation of κB and the of gene by either IL-1α or TNFα to a of that are distinct for (10.Wallach D. Varfolomeev E.E. Malinin N.L. Goltsev Y.V. Kovalenko A.V. Boldin M.P. Annu. Rev. Immunol. 1999; 17: 331-367Crossref PubMed Scopus (1121) Google Scholar, 12.Auron P.E. Cytokine Growth Factor Rev. 1998; 9: 221-237Crossref PubMed Scopus (154) Google Scholar, 13.O'Neill L.A. Greene C. J. Leukocyte Biol. 1998; 63: 650-657Crossref PubMed Scopus (494) Google Scholar). with of and in the components the and the and nuclear of The that IL-1α but not TNFα the stabilization of KC mRNA that IL-1α is to signaling that are not shared with TNFα. In this TNFα and to in some cell types to signaling pathways to the J. Trends Pharmacol. Sci. 1997; 18: 319-322Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, J. J. A. 1999; Google Scholar, S. A. J. Med. 1998; PubMed Scopus Google Scholar). a of this is to the of the signaling pathways J. Trends Pharmacol. Sci. 1997; 18: 319-322Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, J. J. A. 1999; Google Scholar, S. A. J. Med. 1998; PubMed Scopus Google and signaling pathways with of mRNA 1998; PubMed Scopus Google Scholar, J. 1998; PubMed Scopus Google that the of specific and 1991; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, L. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). is specific sequences in the is for sequences in that control transcription, multiple in a mRNA that either or the half-life of the 1998; PubMed Scopus Google Scholar, L. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). regions in both the 5′-UTR and the 3′-UTR of function in cooperative to confer sensitivity to 1998; PubMed Scopus Google Scholar, L. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). The findings and more of the of the sequence regions that are Although both the 5′-UTR and a of the 3′-UTR containing an cluster are required, the of the mRNA only both sequences are is the mRNA and to IL-1α-mediated are by distinct or function as of a to is that the sequence in the KC 3′-UTR that is for and IL-1α sensitivity a AU-rich of four overlapping AUUUA sequence motifs are to of the of many factor and J. Rev. 1995; Google Scholar, Trends Sci. 1995; Full Text PDF PubMed Scopus Google Scholar, D. B. K. R. S. A. Sci. S. A. PubMed Scopus Google Scholar, R. Full Text PDF PubMed Scopus Google Scholar). of the mRNA that of the mRNA the in an mRNA for and this is in part, by the of the N. Biol. 1997; 17: PubMed Scopus Google Scholar). sensitivity for modulation of is a of or is to a is not many that sequence for E. D. Biol. PubMed Scopus Google Scholar, W. K. De D. De K. L. Biol. PubMed Scopus Google Scholar, J. 1997; PubMed Scopus Google Scholar, D. J. 1997; Full Text PDF PubMed Scopus Google Scholar, Biol. 1999; PubMed Scopus Google Scholar). two of The four of or is and to and the of J. 1998; 17: PubMed Scopus Google Scholar, N. J. 1998; 17: PubMed Scopus Google Scholar, J. J. 1999; PubMed Scopus Google Scholar). A is and is a of the nuclear Y. 1998; PubMed Scopus Google Scholar). The of the with an containing mRNA is with mRNA with to the mRNA J. 1998; 17: PubMed Scopus Google Scholar, N. J. 1998; 17: PubMed Scopus Google Scholar, J. J. 1999; PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, 1999; PubMed Scopus Google Scholar). of in the of IL-1α-mediated KC mRNA stabilization the of are to in the development and of inflammatory N. J. Med. 1998; PubMed Scopus Google Scholar, Nature. 1998; PubMed Scopus Google Scholar, 1997; PubMed Google Scholar). The overlapping cell and of many that the control of chemokine an of distinct 1997; PubMed Google Scholar). The expression of many chemokine is to controlled the of transcription, and the are Y. Hamilton T.A. 1994; 2: Scopus Google Scholar, Y. S. Hamilton T.A. J. Immunol. 1995; Google Scholar, Y. L. S. D. Hamilton T.A. J. Google Scholar, Y. Hamilton T.A. J. Biol. Chem. Full Text PDF PubMed Google Scholar, K. S. N. S. K. J. Biol. Chem. Full Text PDF PubMed Google Scholar, T. K. Y. N. K. T. S. Sci. S. A. PubMed Scopus Google Scholar). is that are Indeed, from this and that changes in specific chemokine mRNA an and of the of specific chemokine gene expression Y. Hamilton T.A. 1994; 2: Scopus Google Scholar, T. J. Immunol. 1994; Google Scholar, D. Hamilton T.A. J. Leukocyte Biol. 1998; PubMed Scopus Google Scholar, R. Hamilton T.A. J. Immunol. 1999; 162: Google Scholar). In the the IL-1α-mediated of mouse KC gene The of the IL-1α-mediated stabilization of KC mRNA is a that in and cell The intracellular signaling pathway to the activation of is not for alterations in KC mRNA Nucleotide sequences in the 5′-UTR and 3′-UTR of KC mRNA are both for the and for sensitivity to IL-1α for mRNA and TNFα are to overlapping functional that the to gene expression in a of cell types (5.Vilcek J. Lee T.H. J. Biol. Chem. 1991; 266: 7313-7316Abstract Full Text PDF PubMed Google Scholar, 6.Le J. Vilcek J. Lab. Invest. 1987; 56: 234-248PubMed Google Scholar, 7.Dinarello C.A. Eur. Cytokine. Netw. 1994; 5: 517-531PubMed Google Scholar, 8.Beutler B. J. Invest. Med. 1995; 43: 227-235PubMed Google Scholar). many intracellular signaling components (9.Malinin N.L. Boldin M.P. Kovalenko A.V. Wallach D. Nature. 1997; 385: 540-544Crossref PubMed Scopus (1159) Google Scholar, 10.Wallach D. Varfolomeev E.E. Malinin N.L. Goltsev Y.V. Kovalenko A.V. Boldin M.P. Annu. Rev. Immunol. 1999; 17: 331-367Crossref PubMed Scopus (1121) Google Scholar, 11.Jobin C. Holt L. Bradham C.A. Streetz K. Brenner D.A. Sartor R.B. J. Immunol. 1999; 162: 4447-4454PubMed Google Scholar, 12.Auron P.E. Cytokine Growth Factor Rev. 1998; 9: 221-237Crossref PubMed Scopus (154) Google Scholar, 13.O'Neill L.A. Greene C. J. Leukocyte Biol. 1998; 63: 650-657Crossref PubMed Scopus (494) Google Scholar). both TNFα and are to the activation of and the both were for the of the activation of κB and the of gene by either IL-1α or TNFα to a of that are distinct for (10.Wallach D. Varfolomeev E.E. Malinin N.L. Goltsev Y.V. Kovalenko A.V. Boldin M.P. Annu. Rev. Immunol. 1999; 17: 331-367Crossref PubMed Scopus (1121) Google Scholar, 12.Auron P.E. Cytokine Growth Factor Rev. 1998; 9: 221-237Crossref PubMed Scopus (154) Google Scholar, 13.O'Neill L.A. Greene C. J. Leukocyte Biol. 1998; 63: 650-657Crossref PubMed Scopus (494) Google Scholar). with of and in the components the and the and nuclear of The that IL-1α but not TNFα the stabilization of KC mRNA that IL-1α is to signaling that are not shared with TNFα. In this TNFα and to in some cell types to signaling pathways to the J. Trends Pharmacol. Sci. 1997; 18: 319-322Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, J. J. A. 1999; Google Scholar, S. A. J. Med. 1998; PubMed Scopus Google Scholar). a of this is to the of the signaling pathways J. Trends Pharmacol. Sci. 1997; 18: 319-322Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, J. J. A. 1999; Google Scholar, S. A. J. Med. 1998; PubMed Scopus Google and signaling pathways with of mRNA 1998; PubMed Scopus Google Scholar, J. 1998; PubMed Scopus Google Scholar). that the of specific and 1991; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, L. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). is specific sequences in the is for sequences in that control transcription, multiple in a mRNA that either or the half-life of the 1998; PubMed Scopus Google Scholar, L. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). regions in both the 5′-UTR and the 3′-UTR of function in cooperative to confer sensitivity to 1998; PubMed Scopus Google Scholar, L. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). The findings and more of the of the sequence regions that are Although both the 5′-UTR and a of the 3′-UTR containing an cluster are required, the of the mRNA only both sequences are is the mRNA and to IL-1α-mediated are by distinct or function as of a to is that the sequence in the KC 3′-UTR that is for and IL-1α sensitivity a AU-rich of four overlapping AUUUA sequence motifs are to of the of many factor and J. Rev. 1995; Google Scholar, Trends Sci. 1995; Full Text PDF PubMed Scopus Google Scholar, D. B. K. R. S. A. Sci. S. A. PubMed Scopus Google Scholar, R. Full Text PDF PubMed Scopus Google Scholar). of the mRNA that of the mRNA the in an mRNA for and this is in part, by the of the N. Biol. 1997; 17: PubMed Scopus Google Scholar). sensitivity for modulation of is a of or is to a is not many that sequence for E. D. Biol. PubMed Scopus Google Scholar, W. K. De D. De K. L. Biol. PubMed Scopus Google Scholar, J. 1997; PubMed Scopus Google Scholar, D. 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