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Tristetraprolin Limits Inflammatory Cytokine Production in Tumor-Associated Macrophages in an Mrna Decay− Independent Manner

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Tristetraprolin Limits Inflammatory Cytokine Production in Tumor-Associated Macrophages in an Mrna Decay− Independent Manner Published OnlineFirst July 16, 2015; DOI: 10.1158/0008-5472.CAN-15-0205 Cancer Microenvironment and Immunology Research Tristetraprolin Limits Inflammatory Cytokine Production in Tumor-Associated Macrophages in an mRNA Decay–Independent Manner Franz Kratochvill1,2, Nina Gratz1, Joseph E. Qualls1,2, Lee-Ann Van De Velde1,2, Hongbo Chi2, Pavel Kovarik3, and Peter J. Murray1,2 Abstract Tristetraprolin (TTP) is an inducible zinc finger AU-rich (TAM). However, TTP's effects on AU-rich mRNA stability RNA-binding protein essential for enforcing degradation of were negligible and limited by constitutive p38a MAPK activ- mRNAs encoding inflammatory chemokines and cytokines. ity, which was the main driver of proinflammatory cytokine Most studies on TTP center on the connection between mRNA production in TAMs at the posttranscriptional level. Instead, half-life and inflammatory output, because loss of TTP ampli- elimination of TTP caused excessive protein production of fies inflammation by increasing the stability of AU-rich inflammatory mediators, suggesting TTP-dependent transla- mRNAs. Here, we focused on how TTP controls cytokine and tional suppression of AU-rich mRNAs. Manipulation of the chemokine production in the nonresolving inflammation of p38a–TTP axis in macrophages has significant effects on the cancer using tissue-specific approaches. In contrast with mod- growth of tumors and therefore represents a means to mani- el in vitro macrophage systems, we found constitutive TTP pulate inflammation in the tumor microenvironment. Cancer expression in late-stage tumor-associated macrophages Res; 75(15); 1–11. Ó2015 AACR. Introduction TLR signaling phosphorylates TTP thereby blocking its function and sustaining TNF output (9, 10). In the resolution phase, DUSP Nonresolving inflammation (NRI) underpins most chronic dis- proteins dephosphorylate p38a, which leads to dephosphoryla- eases, including obesity, autoinflammatory diseases, atherosclero- tion of TTP and a rise in TTP activity to eliminate TNF mRNA. IL10, sis, chronic responses to implanted medical devices, chronic or stimulated by TLR signaling to act in an autocrine way, further latent infections, and cancer (1). NRI is caused by aberrant enhances removal of the TNF mRNA because it drives TTP and responses to a persisting entity. The persistence of malignant cells DUSP1 expression in a STAT3-dependent way (7, 11, 12). in cancer, for example, drives the production of hematopoietic cells To begin to understand the signaling pathways involved in from the bone marrow to seed a growing tumor (2). Therefore, a regulating chronic inflammation in tumor-associated macro- challenge of biology and medicine is to understand the cellular and phages (TAM), we used transplantable tumor models with pre- molecular pathways underpinning NRI and how to mitigate their dictable temporal inflammatory responses that can be tracked by effects in chronic diseases. flow cytometry and that are amenable to the use of genetics to In resolving inflammation triggered by TLR signaling, the TNF probe signaling pathways and how they become dysregulated. We mRNA is rapidly produced from poised Pol II at the Tnf promoter focused on how TTP regulates cytokine and chemokine produc- (3–5). TNF protein is made and secreted, followed by a down- tion because inflammatory cytokines are the key drivers of chronic regulation phase where the tristetraprolin (TTP) zinc finger pro- inflammation such as cancer. A key tactic was using a conditional tein, also induced in the early phase of TLR signaling, plays a knockout allele of Zfp36 (encoding TTP) to avoid complications decisive role in eliminating TNF mRNA (6). In model, in vitro À À of systemic inflammation present in conventional Zfp36 / mice systems such as BMDMs the TNF–TTP pathway is controlled by early in development (13–15). Our results show that TTP main- two key factors, p38a MAPK and IL10 (7–9). p38a activated by tains macrophages on a "knife-edge" between counterregulation of inflammation and death. Our results also suggest TTP primarily 1Department of Infectious Diseases, St. Jude Children's Research Hospi- regulates steps beyond mRNA stability such as mRNA translation tal, Memphis, Tennessee. 2Department of Immunology, St. Jude Chil- in macrophages associated with cancer inflammation. dren's Research Hospital, Memphis, Tennessee. 3Max F. Perutz Labora- tories, Center for Molecular Biology,University of Vienna,Vienna, Austria. Materials and Methods Note: Supplementary data for this article are available at Cancer Research Mice Online (http://cancerres.aacrjournals.org/). C57BL/6, Tie2-Cre (B6.Cg-Tg(Tek-cre)1Ywa/J), and LysM-Cre Current address for J.E. Qualls: Cincinnati Children's Hospital Medical Center, (Lyz2tm1(cre)Ifo/J) mice were obtained from The Jackson Laboratory. Cincinnati, OH. À À TTPKO (Zfp36 / ) mice were a gift of P. Blackshear (National Corresponding Author: Peter J. Murray, Infectious Diseases, MS320, Room E8078, Institute of Environmental Health Sciences, Research Triangle Park, fl fl St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105- NC). The TTPDM and Mapk14 ox/ ox mice have been described 3678. Phone: 901-595-3219; Fax: 901-595-3099. E-mail: [email protected] fl fl elsewhere (15, 16). Th-MYCN transgenic (tg; ref. 17) and Rb ox/ ox; fl fl þ doi: 10.1158/0008-5472.CAN-15-0205 p53 ox/ ox;Osx-Cre (mixed background) mice (18) were Ó2015 American Association for Cancer Research. obtained from M. Dyer, St. Jude Children's Research Hospital, www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst July 16, 2015; DOI: 10.1158/0008-5472.CAN-15-0205 Kratochvill et al. A 7 Days 12 Days 17 Days C TAM-A A B Ly6C 80 TAM-C 60% TAMs 70 60 51% D C − 50 36% Ly6G + MHCII 40 B 4 Days 7 Days 12 Days 30 A CD11b % of Ly6C B 20 PAMs 10 8% 4% 5% 0 D C 7 Days 12 Days 17 Days MHCII D TNF TNF 50 800 A A B C 40 B 600 C 30 400 20 MFI − 200 % Positive cells 10 TNF TNF + 0 0 A B C TNF− TNF+ TNF IL1α IL1α 50 200 A A B C 40 B % of max. 150 C 30 100 20 MFI − 50 IL1α % Positive cells 10 IL1α+ 0 0 + A B C IL1α − IL1α IL1α Figure 1. NRI-associated macrophages share a common mode of development and express proinflammatory cytokines. A and B, flow-cytometry plots of CD11bþLy6GÀ myeloid cells isolated from EG7 thymomas (A) or zymosan induced peritonitis (B) at different time points as indicated. Plots are representative for at least two experiments. Gates A to D indicate TAM or peritonitis-associated macrophage (PAM) populations used for sorting experiments or to measure cytokine production by intracellular flow cytometry. C, quantitative analysis of EG7 TAM populations A and C (gated as in A) over time. Values are from one of two independent experiments (n 4); error bars, SEM. D, quantitative analysis of cytokine production by flow cytometry of EG7 TAM populations A to C gated as shown in A. Values from individual mice are either depicted as the percentage of positive cells (left) or median fluorescence intensity (MFI, middle) of þ þ À À TNF or IL1a-positive (TNF and IL1a ) compared with negative (TNF and IL1a ) macrophages within population A to C. Example plots are shown (right) indicating the gating strategy for cells considered positive and negative. Unstained control, gray. Data are mean Æ SEM of two independent experiments (n 2). Memphis, TN. For experiments, sex-matched mice were grouped were purified by Miltenyi magnetic beads according to the man- and used between 6 and 10 weeks. All mice were on a C57BL/6 ufacturer's protocol. background unless indicated otherwise. Mice were used within the Animal Resource Center according to protocols approved by the TAM collection from solid tumors Institutional Animal Care and Use Committee of St. Jude Chil- Solid tumors were minced and digested with 5 mL of fresh dren's Research Hospital. Tumor Digestion Media as described in the Supplementary Mate- rials and Methods. The suspension was then passed through a Zymosan A induced peritonitis 70-mm strainer and cells were overlaid on a 35%/60% percoll Chronic peritonitis was induced by i.p. injection of 10 mg/ gradient. After centrifugation cells were collected from the 35%/ þ mouse of zymosan A (Sigma) as described (19) and CD11b cells 60% interphase and TAMs were isolated by CD11b purification OF2 Cancer Res; 75(15) August 1, 2015 Cancer Research Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst July 16, 2015; DOI: 10.1158/0008-5472.CAN-15-0205 TTP Limits Inflammation in Tumor Macrophages A B C TTP TTP 2 *** *** 3 *** 2 1h LPS BMDM N-TAM O-TAM T-TAM 1 BMDM mRNA TTP mRNA 1 GRB2 0 0 ACDB ns 3 h 1 h 6 h ON T-TAM N-TAM O-TAM D ARE-BPs Rank Within top % 10,000 Zfp36 165 0.37 N-TAM Zfp36L1 383 0.85 8,000 T-TAM G-TAM Zfp36L2 587 1.30 6,000 Hnrnpd 1,108 2.46 4,000 Elavl1 2,657 5.90 Elavl2 9,494 21.08 Signal intensity 2,000 Elavl4 11,975 26.59 0 Tia1 2,804 6.23 TTP Tia1 Khsrp 7,411 16.45 Khsrp Elavl2 Elavl4 Elavl1 Hnrnpd Zfp36L1 Zfp36L2 Figure 2. TTP is highly expressed in selected TAM populations. A, immunoblot analysis of TTP expression in neuroblastoma (N), osteosarcoma (O), and EG7 thymoma (T) TAMs compared with 1 hour LPS-stimulated BMDMs. Blot was reprobed with anti-GRB2 to test for equal loading and represents one of three experiments.B, TTPqRT-PCR of EG7 TAMs sorted for the indicated populations as in Fig.
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