Tristetraprolin Limits Inflammatory Cytokine Production in Tumor-Associated Macrophages in an mRNA Decay-Independent Manner.

Abstract

Tristetraprolin (TTP) is an inducible zinc finger AU-rich RNA-binding protein essential for enforcing degradation of mRNAs encoding inflammatory chemokines and cytokines. Most studies on TTP center on the connection between mRNA half-life and inflammatory output, because loss of TTP amplifies inflammation by increasing the stability of AU-rich mRNAs. Here, we focused on how TTP controls cytokine and chemokine production in the nonresolving inflammation of cancer using tissue-specific approaches. In contrast with model in vitro macrophage systems, we found constitutive TTP expression in late-stage tumor-associated macrophages (TAM). However, TTP's effects on AU-rich mRNA stability were negligible and limited by constitutive p38α MAPK activity, which was the main driver of proinflammatory cytokine production in TAMs at the posttranscriptional level. Instead, elimination of TTP caused excessive protein production of inflammatory mediators, suggesting TTP-dependent translational suppression of AU-rich mRNAs. Manipulation of the p38α-TTP axis in macrophages has significant effects on the growth of tumors and therefore represents a means to manipulate inflammation in the tumor microenvironment.

• Authors: Franz Kratochvill, Nina Gratz, Joseph E Qualls, Lee-Ann Van De Velde, Hongbo Chi, Pavel Kovarik, Peter J Murray
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 15 Pg. 3054-64 (Aug 01 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 26183929 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Cytokines
• Inflammation Mediators
• Tristetraprolin
• Zfp36 protein, mouse
• Mitogen-Activated Protein Kinase 14

Topics

• Animals
• Cytokines (metabolism)
• Inflammation (metabolism, pathology)
• Inflammation Mediators (metabolism)
• Macrophages (metabolism, pathology)
• Mice, Inbred C57BL
• Mice, Transgenic
• Mitogen-Activated Protein Kinase 14 (metabolism)
• Neoplasms, Experimental (metabolism, pathology)
• RNA Processing, Post-Transcriptional
• RNA Stability
• Tristetraprolin (genetics, metabolism)