title: Zinc finger protein tristetraprolin interacts with CCL3 mRNA and regulates tissue inflammation.
abstract: Zinc finger protein tristetraprolin (TTP) modulates macrophage inflammatory activity by destabilizing cytokine mRNAs. In this study, through a screen of TTP-bound mRNAs in activated human macrophages, we have identified CCL3 mRNA as the most abundantly bound TTP target mRNA and have characterized this interaction via conserved AU-rich elements. Compared to the wild-type cells, TTP(-/-) macrophages produced higher levels of LPS-induced CCL3. In addition, the plasma level of CCL3 in TTP(-/-) mice was markedly higher than that in wild-type mice. To determine the in vivo significance of TTP-regulated CCL3, we generated CCL3(-/-)TTP(-/-) double-knockout mice. Along with decreased proinflammatory cytokines in their paw joints, there were significant functional and histologic improvements in the inflammatory arthritis of TTP(-/-) mice when CCL3 was absent, although cachexia, reflecting systemic inflammation, was notably unaffected. Furthermore, the marked exacerbation of aortic plaque formation caused by TTP deficiency in the APOE(-/-) mouse model of atherosclerosis was also rescued by disrupting CCL3. Taken together, our data indicate that the interaction between TTP and CCL3 mRNA plays an important role in modulating localized inflammatory processes in tissues that are dissociated from the systemic manifestations of chronic inflammation.
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ju-Gyeong
authors.initials: JG
authors.lastname: Kang
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Amar
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.forename: Jaeyul
authors.initials: J
authors.lastname: Kwon
authors.forename: Perry J
authors.initials: PJ
authors.lastname: Blackshear
authors.forename: Ping-yuan
authors.initials: PY
authors.lastname: Wang
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hwang
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D054405:Chemokine CCL3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D051816:Tristetraprolin / Q000276:immunology / Q000378:metabolism*
chemical_list: D054405:Chemokine CCL3; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051816:Tristetraprolin