Cytokines are critical mediators of inflammation and host defenses. Regulation of cytokines can occur at various stages of gene expression, including transcription, mRNA export, and post- transcriptional and translational levels. Among these modes of regulation, post-transcriptional regulation has been shown to play a vital role in controlling the expression of cytokines by modulating mRNA stability. The stability of cytokine mRNAs, including TNFα, IL-6, and IL-8, has been reported to be altered by the presence of AU-rich elements (AREs) located in the 3′-untranslated regions (3′UTRs) of the mRNAs. Numerous RNA-binding proteins and microRNAs bind to these 3′UTRs to regulate the stability and/or translation of the mRNAs. Thus, this paper describes the cooperative function between RNA-binding proteins and miRNAs and how they regulate AU-rich elements containing cytokine mRNA stability/degradation and translation. These mRNA control mechanisms can potentially influence inflammation as it relates to oral biology, including periodontal diseases and oral pharyngeal cancer progression.

Anderson P (2009). Intrinsic mRNA stability helps compose the inflammatory symphony. Nat Immunol 10:233-234. Crossref, Medline
Audic Y, Hartley RS (2004). Post-transcriptional regulation in cancer. Biol Cell 96:479-498. Crossref, Medline
Bak RO, Mikkelsen JG (2010). Regulation of cytokines by small RNAs during skin inflammation. J Biomed Sci 17:53. Crossref, Medline
Bakheet T, Williams BR, Khabar KS (2006). ARED 3.0: the large and diverse AU-rich transcriptome. Nucleic Acids Res 34: D111-114. Crossref, Medline
Bhattacharyya SN, Habermacher R, Martine U, Closs EI, Filipowicz W (2006). Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell 125:1111-1124. Crossref, Medline
Caput D, Beutler B, Hartog K, Thayer R, Brown-Shimer S, Cerami A (1986). Identification of a common nucleotide sequence in the 3′-untranslated region of mRNA molecules specifying inflammatory mediators. Proc Natl Acad Sci USA 83:1670-1674. Crossref, Medline
Carballo E, Lai WS, Blackshear PJ (1998). Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science 281:1001-1005. Crossref, Medline
Cha JD, Li S, Cha IH (2011). Association between expression of embryonic lethal abnormal vision-like protein HuR and cyclooxygenase-2 in oral squamous cell carcinoma. Head Neck 33:627-637. Crossref, Medline
Chen S, Fribley A, Wang CY (2002). Potentiation of tumor necrosis factor-mediated apoptosis of oral squamous cell carcinoma cells by adenovirus-mediated gene transfer of NF-kappaB inhibitor. J Dent Res 81:98-102. Abstract
Cheneval D, Kastelic T, Fuerst P, Parker CN (2010). A review of methods to monitor the modulation of mRNA stability: a novel approach to drug discovery and therapeutic intervention. J Biomol Screen 15: 609-622. Link
Cho NP, Han HS, Soh Y, Son HJ (2007). Overexpression of cyclooxygenase-2 correlates with cytoplasmic HuR expression in salivary mucoepidermoid carcinoma but not in pleomorphic adenoma. J Oral Pathol Med 36:297-303. Crossref, Medline
Choi HJ, Yang H, Park SH, Moon Y (2009). HuR/ELAVL1 RNA binding protein modulates interleukin-8 induction by muco-active ribotoxin deoxynivalenol. Toxicol Appl Pharmacol 240:46-54. Crossref, Medline
Deleault KM, Skinner SJ, Brooks SA (2008). Tristetraprolin regulates TNF TNF-alpha mRNA stability via a proteasome dependent mechanism involving the combined action of the ERK and p38 pathways. Mol Immunol 45:13-24. Crossref, Medline
Eberhardt W, Doller A, Akool el-S, Pfeilschifter J (2007). Modulation of mRNA stability as a novel therapeutic approach. Pharmacol Ther 114:56-73. Crossref, Medline
El Gazzar M, McCall CE (2010). MicroRNAs distinguish translational from transcriptional silencing during endotoxin tolerance. J Biol Chem 285:20940-20951. Crossref, Medline
Friedman RC, Farh KK, Burge CB, Bartel DP (2009). Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92-105. Crossref, Medline
Glorian V, Maillot G, Poles S, Iacovoni JS, Favre G, Vagner S (2011). HuR-dependent loading of miRNA RISC to the mRNA encoding the Ras-related small GTPase RhoB controls its translation during UV-induced apoptosis. Cell Death Differ 18:1692-1701. Crossref, Medline
Guo H, Ingolia NT, Weissman JS, Bartel DP (2010). Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466:835-840. Crossref, Medline
Hamilton TA, Novotny M, Datta S, Mandal P, Hartupee J, Tebo J, . (2007). Chemokine and chemoattractant receptor expression: post-transcriptional regulation. J Leukoc Biol 82:213-219. Crossref, Medline
Han J, Brown T, Beutler B (1990). Endotoxin-responsive sequences control cachectin/tumor necrosis factor biosynthesis at the translational level. J Exp Med 171:465-475. Crossref, Medline
Hao S, Baltimore D (2009). The stability of mRNA influences the temporal order of the induction of genes encoding inflammatory molecules. Nat Immunol 10:281-288. Crossref, Medline
Hirth A, Skapenko A, Kinne RW, Emmrich F, Schulze-Koops H, Sack U (2002). Cytokine mRNA and protein expression in primary-culture and repeated-passage synovial fibroblasts from patients with rheumatoid arthritis. Arthritis Res 4:117-125. Crossref, Medline
Jafarifar F, Yao P, Eswarappa SM, Fox PL (2011). Repression of VEGFA by CA-rich element-binding microRNAs is modulated by hnRNP L. EMBO J 30:1324-1334. Crossref, Medline
Jing Q, Huang S, Guth S, Zarubin T, Motoyama A, Chen J, . (2005). Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell 120:623-634. Crossref, Medline
Katsanou V, Papadaki O, Milatos S, Blackshear PJ, Anderson P, Kollias G, . (2005). HuR as a negative posttranscriptional modulator in inflammation. Mol Cell 19:777-789. Crossref, Medline
Keller ET, Wanagat J, Ershler WB (1996). Molecular and cellular biology of interleukin-6 and its receptor. Front Biosci 1:d340-d357. Crossref, Medline
Khabar KS (2005). The AU-rich transcriptome: more than interferons and cytokines, and its role in disease. J Interferon Cytokine Res 25:1-10. Crossref, Medline
Kim HH, Kuwano Y, Srikantan S, Lee EK, Martindale JL, Gorospe M (2011). HuR recruits let-7/RISC to repress c-Myc expression. Genes Dev 23:1743-1748. Crossref
Kirkwood KL, Rossa CJr (2009). The potential of p38 MAPK inhibitors to modulate periodontal infections. Curr Drug Metab 10:55-67. Crossref, Medline
Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G (1999). Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10:387-398. Crossref, Medline
Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR (1991). TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem 266:12866-12872. Medline
Lasa M, Mahtani KR, Finch A, Brewer G, Saklatvala J, Clark AR (2000). Regulation of cyclooxygenase 2 mRNA stability by the mitogen-activated protein kinase p38 signaling cascade. Mol Cell Biol 20:4265-4274. Crossref, Medline
Levy AP, Levy NS, Iliopoulos O, Jiang C, Kaplin WGJr, Goldberg MA (1997). Regulation of vascular endothelial growth factor by hypoxia and its modulation by the von Hippel-Lindau tumor suppressor gene. Kidney Int 51:575-578. Crossref, Medline
Levy NS, Chung S, Furneaux H, Levy AP (1998). Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. J Biol Chem 273:6417-6423. Crossref, Medline
Li A, Dubey S, Varney ML, Dave BJ, Singh RK (2003). IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol 170:3369-3376. Crossref, Medline
Ma F, Liu X, Li D, Wang P, Li N, Lu L, . (2010). MicroRNA-466l upregulates IL-10 expression in TLR-triggered macrophages by antagonizing RNA-binding protein tristetraprolin-mediated IL-10 mRNA degradation. J Immunol 184:6053-6059. Crossref, Medline
Meisner NC, Hintersteiner M, Mueller K, Bauer R, Seifert JM, Naegeli HU, . (2007). Identification and mechanistic characterization of low-molecular-weight inhibitors for HuR. Nat Chem Biol 3:508-515. Crossref, Medline
O’Neill LA, Sheedy FJ, McCoy CE (2011). MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat Rev Immunol 11:163-175. Crossref, Medline
Palanisamy V, Park NJ, Wang J, Wong DT (2008). AUF1 and HuR proteins stabilize interleukin-8 mRNA in human saliva. J Dent Res 87:772-776. Link
Patil CS, Liu M, Zhao W, Coatney DD, Li F, VanTubergen EA, . (2008). Targeting mRNA stability arrests inflammatory bone loss. Mol Ther 16:1657-1664. Crossref, Medline
Phillips K, Kedersha N, Shen L, Blackshear PJ, Anderson P (2004). Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor alpha, cyclooxygenase 2, and inflammatory arthritis. Proc Natl Acad Sci USA 101:2011-2016. Crossref, Medline
Pries R, Wollenberg B (2006). Cytokines in head and neck cancer. Cytokine Growth Factor Rev 17:141-146. Crossref, Medline
Rana TM (2007). Illuminating the silence: understanding the structure and function of small RNAs. Nat Rev Mol Cell Biol 8:23-36. Crossref, Medline
Sadri N, Schneider RJ (2009). Auf1/Hnrnpd-deficient mice develop pruritic inflammatory skin disease. J Invest Dermatol 129:657-670. Crossref, Medline
Sengupta S, Jang BC, Wu MT, Paik JH, Furneaux H, Hla T (2003). The RNA-binding protein HuR regulates the expression of cyclooxygenase-2. J Biol Chem 278:25227-25233. Crossref, Medline
Shaw G, Kamen R (1986). A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 46:659-667. Crossref, Medline
Souza LS, Machado SH, Brenol CV, Brenol JC, Xavier RM (2008). Growth velocity and interleukin 6 concentrations in juvenile idiopathic arthritis. J Rheumatol 35:2265-2271. Crossref, Medline
St John MA, Li Y, Zhou X, Denny P, Ho CM, Montemagno C, . (2004). Interleukin 6 and interleukin 8 as potential biomarkers for oral cavity and oropharyngeal squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 130:929-935. Crossref, Medline
Steitz JA, Vasudevan S (2009). miRNPs: versatile regulators of gene expression in vertebrate cells. Biochem Soc Trans 37(Pt 5):931-935. Crossref, Medline
Stoecklin G, Gross B, Ming XF, Moroni C (2003). A novel mechanism of tumor suppression by destabilizing AU-rich growth factor mRNA. Oncogene 22:3554-3561. Crossref, Medline
Stoecklin G, Mayo T, Anderson P (2006). ARE-mRNA degradation requires the 5′-3′ decay pathway. EMBO Rep 7:72-77. Crossref, Medline
Subramaniam D, Ramalingam S, May R, Dieckgraefe BK, Berg DE, Pothoulakis C, . (2008). Gastrin-mediated interleukin-8 and cyclooxygenase-2 gene expression: differential transcriptional and posttranscriptional mechanisms. Gastroenterology 134:1070-1082. Crossref, Medline
Sully G, Dean JL, Wait R, Rawlinson L, Santalucia T, Saklatvala J, . (2004). Structural and functional dissection of a conserved destabilizing element of cyclo-oxygenase-2 mRNA: evidence against the involvement of AUF-1 [AU-rich element/poly(U)-binding/degradation factor-1], AUF-2, tristetraprolin, HuR (Hu antigen R) or FBP1 (far-upstream-sequence-element-binding protein 1). Biochem J 377(Pt 3):629-639. Medline
Taylor GA, Carballo E, Lee DM, Lai WS, Thompson MJ, Patel DD, . (1996). A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity 4:445-454. Crossref, Medline
Trikha M, Corringham R, Klein B, Rossi JF (2003). Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res 9:4653-4665. Medline
van Kempen LC, de Visser KE, Coussens LM (2006). Inflammation, proteases and cancer. Eur J Cancer 42:728-734. Crossref, Medline
Van Tubergen E, Vander Broek R, Lee J, Wolf G, Carey T, Bradford C, . (2011). Tristetraprolin regulates interleukin-6, which is correlated with tumor progression in patients with head and neck squamous cell carcinoma. Cancer 117:2677-2689. Crossref, Medline
Vasudevan S, Steitz JA (2007). AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2. Cell 128:1105-1118. Crossref, Medline
Vasudevan S, Tong Y, Steitz JA (2007). Switching from repression to activation: microRNAs can up-regulate translation. Science 318:1931-1934. Crossref, Medline
Villarete LH, Remick DG (1996). Transcriptional and post-transcriptional regulation of interleukin-8. Am J Pathol 149:1685-1693. Medline
Wilusz CJ, Wormington M, Peltz SW (2001). The cap-to-tail guide to mRNA turnover. Nat Rev Mol Cell Biol 2:237-246. Crossref, Medline
Yu H, Sun Y, Haycraft C, Palanisamy V, Kirkwood KL (2011). MKP-1 regulates cytokine mRNA stability through selectively modulation subcellular translocation of AUF1. Cytokine 56:245-255. Crossref, Medline

Vol 91, Issue 7, 2012

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Control of Cytokine mRNA Expression by RNA-binding Proteins and microRNAs

V. Palanisamy1, #, A. Jakymiw1, #, E.A. Van Tubergen3, #, N.J. D’Silva3, 4, K.L. Kirkwood12*Department of Craniofacial Biology, Medical University of South Carolina, Charleston, SC, USADepartment of Microbiology and Immunology, Center for Oral Health Research, College of Dental Medicine, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USADepartment of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI, USADepartment of Pathology, University of Michigan, Ann Arbor, MI, USA

Journal of Dental Research

Vol 91, Issue 7, pp. 651 - 658

First published date: February-01-2012

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V. Palanisamy, A. Jakymiw, E.A. Van Tubergen, N.J. D’Silva, and K.L. Kirkwood
Journal of Dental Research 2012 91:7, 651-658

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