[雙語翻譯]--醫(yī)學(xué)外文翻譯--免疫和疾病中的mir-146（英文）

1、SAGE-Hindawi Access to Research Molecular Biology International Volume 2011, Article ID 437301, 7 pages doi:10.4061/2011/437301Review ArticleMiR-146a in Immunity and DiseaseNicole Rusca and Silvia MonticelliInstitute for

2、 Research in Biomedicine, Via Vincenzo Vela 6, 6500 Bellinzona, SwitzerlandCorrespondence should be addressed to Silvia Monticelli, silvia.monticelli@irb.unisi.chReceived 17 December 2010; Accepted 17 February 2011Academ

3、ic Editor: Alessandro DesideriCopyright © 2011 N. Rusca and S. Monticelli. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and

4、 reproduction in any medium, provided the original work is properly cited.MicroRNAs (miRNAs) are regulatory molecules able to influence all aspects of the biology of a cell. They have been associated with diseases such a

5、s cancer, viral infections, and autoimmune diseases, and in recent years, they also emerged as important regulators of immune responses. MiR-146a in particular is rapidly gaining importance as a modulator of differentiat

6、ion and function of cells of the innate as well as adaptive immunity. Given its importance in regulating key cellular functions, it is not surprising that miR-146a expression was also found dysregulated in different type

7、s of tumors. In this paper, we summarize recent progress in understanding the role of miR-146a in innate and adaptive immune responses, as well as in disease.1. IntroductionMicroRNAs (miRNAs) represent a pervasive featur

8、e of all cells, as they regulate large fractions of the cell’s tran- scriptome. So far, 672 mouse miRNAs and 1048 human miRNAs have been described in the miRBase database (http://www.mirbase.org/, release Sept. 2010) wit

9、h each miRNA potentially regulating the expression of hundreds of target genes, highlighting the extent of this form of regulation [1]. Whereas some miRNAs are widely expressed, others exhibit only limited developmental

10、stage-, tissue-, or cell type-specific patterns [2]. Similar to any other mammalian cell type, cells of the immune system rely on miRNAs to regulate lineage commitment, proliferation, migration, and differentiation. In m

11、ost cases, these activities are orchestrated by both ubiquitously expressed and cell type-specific miRNA species [3–7]. The importance of miRNAs in regulating differentiation and function of immune cells is underlined by

12、 the phenotypical perturbations that occur when miRNA expression is altered. Given the emerging roles of miRNAs in modulating immune responses, it is likely that any dysreg- ulation of miRNA expression may contribute to

13、the patho- genesis of autoimmune diseases, chronic inflammation, and malignancies. Indeed, several human diseases have now been associated with dysregulated miRNA expression, and miRNAs have been shown to function both a

14、s oncogenes and tumor suppressor genes [8, 9]. MiR-146a has been recentlyshown to be an important modulator of differentiation and function of cells of innate as well as adaptive immunity. Here, we summarize recent progr

15、ess in understanding the role of miR-146a in immune responses and in disease (see also Table 1).2. What Are MicroRNAs?MiRNAs are small (20–25 nucleotides), noncoding RNA molecules involved in posttranscriptional gene reg

16、ulation. They derive from primary transcripts (pri-miRNA) that are processed into hairpin precursors (pre-miRNAs) within the nucleus of the cell by the Microprocessor complex, which includes the RNAseIII enzyme Drosha. P

17、re-miRNAs are translocated into the cytoplasm and processed by Dicer into their mature form (for a recent review see [25]). An exception to this rule is represented by the less abundant “mirtrons” , that bypass Drosha an

18、d are processed only by Dicer [26]. Mature miRNAs loaded onto the RNA-induced silencing complex (RISC) recognize sites located mostly in the 3? untranslated region (3? UTR) of target mRNAs through canonical base-pairing

19、between the seed sequence of the miRNA (nucleotides 2–8 at its 5? end) and its complementary sequence in the target mRNA. This leads to a block in translation with or without destabilization and degradation of the target

20、ed mRNA. MiRNAs modulate aMolecular Biology International 3T-cell subsets. Indeed, T cells lacking Dicer showed increased differentiation to the Th1 subset with a correspondingly reduced polarization to Th2 [29]. Adding

21、to the complexity of gene regulatory networks, proliferating T cells express genes with shorter 3?UTRs than those expressed in resting T cells, making these mRNAs less susceptible to regulation by miRNAs due to the loss

22、of miRNA binding sites [41]. Finally, individual miRNAs were also shown to play important roles in T-cell differentiation and function. For example, miR-181a, which is upregulated during T-cell development, was shown to

23、enhance T-cell receptor (TCR) signalling strength by directly targeting a number of protein phos- phatases [32], while mice lacking miR-155 showed an altered Th1/Th2 polarization with a bias towards Th2, indicating that

24、miR-155 promotes differentiation towards Th1 cells [35].As for the role of miR-146a in T cells, by analyzing the expression of miRNAs in highly purified subsets of cells of the immune system, we showed that miR-146a is o

25、ne of the very few miRNAs differentially expressed between Th1 and Th2 cells in the mouse, suggesting that it might be involved in fate determination of these cells [5]. Recent work performed in miR-146a-deficient mice s

26、howed an increase in the percentage of INFγ-producing T-cell subset in the absence of miR-146a [10]. In human T cells, miR-146a is expressed at low levels in na¨ ?ve T lymphocytes while it is abundantly expressed in

27、 memory T cells and it is induced upon TCR stimulation, consistent with its expression being dependent on NF-κB induction [12, 13]. Indeed, NF-κB and c-ETS-binding sites were shown to be required for the induction of miR

28、-146a transcription in human T cells, and such induction potentially modulated cell death in these cells by targeting FADD and by impairing both AP-1 activity and IL-2 production [13]. Treg cells constitute a specialized

29、 T-cell subset able to maintain immune homeostasis by limiting the inflammatory responses, and their suppressive function is indispensable for immune homeostasis and survival of higher organisms. Recently, Lu and colleag

30、ues reported that miR-146a is among the miRNAs prevalently expressed in Treg cells and showed that it is critical for Treg functions. Indeed, deficiency of miR-146a resulted in increased numbers but impaired function of

31、Treg cells and as a consequence, breakdown of immunological tolerance with massive lymphocyte activation, and tissue infiltration in several organs [10]. The immune-mediated lesions induced by the lack of miR-146a in Tre

32、gs were dependent on INFγ and Stat1.4. MiR-146 in Innate Immunity and Nonimmune SystemsCells of the innate immune system, such as granulocytes, natural killer (NK) cells, monocytes, and macrophages, provide an important

33、first line of defense for the organism against invading pathogens. MiRNAs have been implicated in both the development and functions of innate immune cells. For example, the macrophage inflammatory response to infection

34、involves the upregulation of several miRNAs, suchTLR4AdaptermoleculesIKK complexP PIRAK1TRAF6CytoplasmNucleus pri-miR-146amiR-146a RISC complexIκBαNF-κBNF-κBFigure 1: MiR-146a negatively regulates signal transduction pat

35、h- ways leading to NF-κB activation. Upon activation of a cell surface receptor such as TLR4, a molecular cascade including TRAF6 and IRAK1 leads to IκBα phosphorylation and degradation and to NF-κB activation and nuclea

36、r translocation [12, 42]. NF-κB activation induces transcription of many genes, including pri-miR- 146a. Once translocated to the cytoplasm and loaded onto the RISC complex, mature miR-146a contributes to attenuate recep

37、tor signaling through the downmodulation of IRAK1 and TRAF6.as miR-155, miR-146, miR-147, miR-21, and miR-9 [12, 43– 46]. Several studies linked miR-146a expression to NF-κB signaling within the innate immune system (Fig

38、ure 1) and were initiated by a study showing that miR-146a is quickly induced upon activation of human monocytes [12]. In this study, miR-146a was found to be inducible upon stimulation with LPS in a NF-κB-dependent mann

39、er, and to target the TNF receptor-associated factor 6 (TRAF6) and IL-1 receptor- associated kinase 1 (IRAK1) genes. These genes encode two key adapter molecules downstream of cytokine and Toll- like receptors (TLR), poi

40、nting towards a role for miR-146a in controlling signaling from these receptors through a negative feedback regulatory loop involving downregulation of TRAF6 and IRAK1 [12]. It was also suggested that miR-146a contribute

41、s to the establishment of endotoxin tolerance in monocytes and to the regulation of TNFα production [14]. In this context, miR-146a would therefore act as a tuning mechanism to prevent an overstimulated inflammatory stat

42、e. In human Langerhans cells (LCs), miR- 146a was found to be constitutively expressed at high levels, as compared to interstitial dendritic cells (intDCs) [15]. In these cells, high miR-146a expression was induced by th