Zinc finger protein TTP interacts with CCL3 mRNA and regulates inflammatory diseases

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NHLBI	IMMUNO/INFLAM-13

Authors

• JG Kang
• MJ Amar
• AT Remaley
• J Kwon
• PJ Blackshear
• PY Wang
• PM Hwang

Abstract

Background: Post-transcriptional regulation of cytokine mRNAs plays a critical role in determining the outcome of common inflammatory diseases. Zinc finger protein tristetraprolin (TTP) modulates macrophage inflammatory activity by destabilizing cytokine mRNAs. Methods and Results: Through a global screen of TTP-bound mRNAs in activated human macrophages, we have identified CC chemokine ligand 3 (CCL3) mRNA as the most abundantly bound TTP target mRNA and have characterized this interaction via conserved AU-rich elements. To determine the in vivo significance of TTP-regulated CCL3, we deleted CCL3 in TTP-/- 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. Conclusions: 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.

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