Modulation of miR-155 and miR-125b Levels following Lipopolysaccharide/TNF-α Stimulation and Their Possible Roles in Regulating the Response to Endotoxin Shock1

We report here that miR-155 and miR-125b play a role in innate immune response. LPS stimulation of mouse Raw 264.7 macrophages resulted in the up-regulation of miR-155 and down-regulation of miR-125b levels. The same changes also occurred when C57BL/6 mice were i.p. injected with LPS. Furthermore, the levels of miR-155 and miR-125b in Raw 264.7 cells displayed oscillatory changes in response to TNF-α. These changes were impaired by pretreating the cells with the proteasome inhibitor MG-132, suggesting that these two microRNAs (miRNAs) may be at least transiently under the direct control of NF-κB transcriptional activity. We show that miR-155 most probably directly targets transcript coding for several proteins involved in LPS signaling such as the Fas-associated death domain protein (FADD), IκB kinase ε (IKKε), and the receptor (TNFR superfamily)-interacting serine-threonine kinase 1 (Ripk1) while enhancing TNF-α translation. In contrast, miR-125b targets the 3′-untranslated region of TNF-α transcripts; therefore, its down-regulation in response to LPS may be required for proper TNF-α production. Finally, Eμ-miR-155 transgenic mice produced higher levels of TNF-α when exposed to LPS and were hypersensitive to LPS/d-galactosamine-induced septic shock. Altogether, our data suggest that the LPS/TNF-α-dependent regulation of miR-155 and miR-125b may be implicated in the response to endotoxin shock, thus offering new targets for drug design.

[1]  B. Haynes,et al.  A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. , 1996, Immunity.

[2]  Anton J. Enright,et al.  Requirement of bic/microRNA-155 for Normal Immune Function , 2007, Science.

[3]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[4]  C. Benz,et al.  Coordinate Suppression of ERBB2 and ERBB3 by Enforced Expression of Micro-RNA miR-125a or miR-125b* , 2007, Journal of Biological Chemistry.

[5]  Stefano Volinia,et al.  Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[6]  David Baltimore,et al.  MicroRNA-155 is induced during the macrophage inflammatory response , 2007, Proceedings of the National Academy of Sciences.

[7]  Holger Heine,et al.  Molecular mechanisms of endotoxin activity , 1995, Archives of Microbiology.

[8]  D. Goeddel,et al.  TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. , 1996, Immunity.

[9]  A. Hoffmann,et al.  The I (cid:1) B –NF-(cid:1) B Signaling Module: Temporal Control and Selective Gene Activation , 2022 .

[10]  B. Beutler,et al.  The essential role of the UA-rich sequence in endotoxin-induced cachectin/TNF synthesis. , 1990, European cytokine network.

[11]  C. Jobin,et al.  Suppression of NF-kappaB-dependent proinflammatory gene expression in human RPE cells by a proteasome inhibitor. , 1999, Investigative ophthalmology & visual science.

[12]  H. S. Warren,et al.  Toll-like receptors. , 2005, Critical care medicine.

[13]  C. Janeway,et al.  Innate immune recognition. , 2002, Annual review of immunology.

[14]  C. Croce,et al.  A microRNA expression signature of human solid tumors defines cancer gene targets , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Shizuo Akira,et al.  Toll-like Receptor Signaling* , 2003, Journal of Biological Chemistry.

[16]  N. Rajewsky,et al.  Regulation of the Germinal Center Response by MicroRNA-155 , 2007, Science.

[17]  P. Anderson,et al.  TIA‐1 is a translational silencer that selectively regulates the expression of TNF‐α , 2000 .

[18]  Jianke Zhang,et al.  Conditional Fas-Associated Death Domain Protein (FADD):GFP Knockout Mice Reveal FADD Is Dispensable in Thymic Development but Essential in Peripheral T Cell Homeostasis1 , 2005, The Journal of Immunology.

[19]  K. Mahtani,et al.  The 3′ Untranslated Region of Tumor Necrosis Factor Alpha mRNA Is a Target of the mRNA-Stabilizing Factor HuR , 2001, Molecular and Cellular Biology.

[20]  T. Manser,et al.  The Fas-Associated Death Domain Protein Is Required in Apoptosis and TLR-Induced Proliferative Responses in B Cells1 , 2006, The Journal of Immunology.

[21]  Wayne Tam,et al.  Accumulation of miR-155 and BIC RNA in human B cell lymphomas. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[22]  L. Hood,et al.  Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway. , 1997, Immunity.

[23]  T. Mak,et al.  Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection , 1993, Cell.

[24]  C. Aghajanian,et al.  Posttranscriptional regulation of protein expression in human epithelial carcinoma cells by adenine-uridine-rich elements in the 3'-untranslated region of tumor necrosis factor-alpha messenger RNA. , 1997, Cancer research.

[25]  Lin He,et al.  MicroRNAs: small RNAs with a big role in gene regulation , 2004, Nature Reviews Genetics.

[26]  B. Seed,et al.  RIP mediates tumor necrosis factor receptor 1 activation of NF‐kappaB but not Fas/APO‐1‐initiated apoptosis. , 1996, The EMBO journal.

[27]  David Baltimore,et al.  Targeted disruption of the p50 subunit of NF-κB leads to multifocal defects in immune responses , 1995, Cell.

[28]  W. Yeh,et al.  Ubiquitination of RIP1 Regulates an NF-κB-Independent Cell-Death Switch in TNF Signaling , 2007, Current Biology.

[29]  M. Bukrinsky,et al.  Relative Contribution of Transcription and Translation to the Induction of Tumor Necrosis Factor-α by Lipopolysaccharide* , 1998, The Journal of Biological Chemistry.

[30]  Ligang Wu,et al.  MicroRNAs direct rapid deadenylation of mRNA. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[31]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[32]  M. Gaestel,et al.  MAPKAP kinase 2 is essential for LPS-induced TNF-α biosynthesis , 1999, Nature Cell Biology.

[33]  V. Ambros.  The functions of animal microRNAs , 2004, Nature.

[34]  Qiang Sun,et al.  Nuclear Accumulation of cRel following C-Terminal phosphorylation by TBK1/IKKε1 , 2006, The Journal of Immunology.

[35]  Claus Scheidereit,et al.  IκB kinase complexes: gateways to NF-κB activation and transcription , 2006, Oncogene.

[36]  K. Anderson,et al.  Toll signaling pathways in the innate immune response. , 2000, Current opinion in immunology.

[37]  G. Kollias,et al.  TNF-α Induction by LPS Is Regulated Posttranscriptionally via a Tpl2/ERK-Dependent Pathway , 2000, Cell.

[38]  C. Croce,et al.  An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[39]  W. Reutter,et al.  Galactosamine-induced sensitization to the lethal effects of endotoxin. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[40]  D. Baltimore,et al.  NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses , 2006, Proceedings of the National Academy of Sciences.

[41]  M. Fink,et al.  Laboratory models of sepsis and septic shock. , 1990, The Journal of surgical research.

[42]  G. Kollias,et al.  Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response , 1996, The Journal of experimental medicine.

[43]  G. Kollias,et al.  Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. , 1999, Immunity.

[44]  J. Parrillo.  Pathogenetic mechanisms of septic shock. , 1993, The New England journal of medicine.

[45]  Georges Huez,et al.  Identification of TIAR as a Protein Binding to the Translational Regulatory AU-rich Element of Tumor Necrosis Factor α mRNA* , 1999, The Journal of Biological Chemistry.

[46]  C. Dinarello,et al.  Anticytokine strategies in the treatment of the systemic inflammatory response syndrome. , 1993, JAMA.

[47]  A. Varin,et al.  Histone Deacetylase 3, a Class I Histone Deacetylase, Suppresses MAPK11-Mediated Activating Transcription Factor-2 Activation and Represses TNF Gene Expression1 , 2004, The Journal of Immunology.