【讨论】microRNA与树突状细胞
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2429
请教各位大侠：
有没有研究microRNA与树突状细胞免疫功能方面的？现在microRNA的研究已经遍及肿瘤，免疫，心血管疾病，病毒等，如miR-155,有关它与免疫的研究，本人看的几篇文献主要是利用转基因技术敲除小鼠体内Bic基因（miR-155系BIC基因的表达产物，产生于活化的B细胞、T细胞、巨噬细胞、树突状细胞等），检测bic／miR-155-/-小鼠B,T,DC细胞分化，成熟，活化情况，及功能改变等。
miR-155与肿瘤免疫之间的联系，miR-155缺陷或者增强的肿瘤组织中免疫细胞（T细胞、B细胞和树突状细胞）及免疫因子的改变情况？请问有高手做这方面研究没？可以从哪些水平进行？本人正在苦苦挣扎，找不到方向，诚请指点，致谢！
有没有研究microRNA与树突状细胞免疫功能方面的？现在microRNA的研究已经遍及肿瘤，免疫，心血管疾病，病毒等，如miR-155,有关它与免疫的研究，本人看的几篇文献主要是利用转基因技术敲除小鼠体内Bic基因（miR-155系BIC基因的表达产物，产生于活化的B细胞、T细胞、巨噬细胞、树突状细胞等），检测bic／miR-155-/-小鼠B,T,DC细胞分化，成熟，活化情况，及功能改变等。
miR-155与肿瘤免疫之间的联系，miR-155缺陷或者增强的肿瘤组织中免疫细胞（T细胞、B细胞和树突状细胞）及免疫因子的改变情况？请问有高手做这方面研究没？可以从哪些水平进行？本人正在苦苦挣扎，找不到方向，诚请指点，致谢！
提供一篇综述，希望有所启发。
MicroRNA in the immune system, microRNA as an immune system
Immunology
Volume 127, Issue 3, Pages 291-298
MicroRNA in the immune system, microRNA as an immune system
Immunology
Volume 127, Issue 3, Pages 291-298
另外，这篇文章想必你也看过了。可以追踪一下作者的文章或者引用此文的文献。
Sci. STKE, 22 May 2007
Vol. 2007, Issue 387, p. pe25
Micromanagement During the Innate Immune Response
Innate immunity, a well-studied physiological response to bacterial, viral, and other pathogens, is of crucial importance to the survival of organisms as different as humans and flies. The innate immune response is initiated by the binding of a large array of ligands to membrane-associated pathogen recognition receptor proteins known as Toll-like receptors (TLRs), or by treatment with certain cytokines. Recent microarray studies have shown that one consequence of activation of mouse macrophages is an increased accumulation of one or a few microRNAs (miRNAs), specifically miR-155 (1).
miRNAs are small (~22 nucleotides) yet powerful regulators of gene expression that function primarily by reducing the abilities of specific mRNAs to direct the synthesis of their encoded proteins (2). The abundances of particular miRNAs in cells are subject to change in response to physiological stimuli, thereby supporting the normal progression through sequential stages of development or the maintenance of homeostasis (3). However, accumulation of inappropriate amounts of a miRNA can lead to pathologies, notably cancer (4).
One of the first miRNAs associated with cancer was miR-155 [summarized in ( 5)]. This "onco-miRNA" is processed from the third exon of BIC (B cell integration cluster) RNA, which was originally identified as a spliced and polyadenylated but noncoding RNA (ncRNA), ~1700 nucleotides long, accumulating in certain chicken B cell lymphomas. In lymphomas that developed upon infection with avian leukosis virus (ALV), synthesis of BIC RNA was directed by transcription from the integrated ALV provirus into the adjacent cellular BIC gene.
Although it was initially unclear how a large ncRNA affected the development of cancer, a phylogenetically conserved structured region was proposed to be important (5); this region was later found to encode miR-155 ( 6 ), which has a direct role in cancer. Initially, Tam and colleagues (7) showed that expression of the region of BIC RNA containing the hairpin precursor of miR-155 accelerates formation of myc-dependent lymphomas in chickens. More recently, Croce and collaborators ( 8 ) reported that overexpression of miR-155 in pre-B cells of transgenic mice greatly promotes the development of B cell malignancies. The BIC gene has its own promoter, and elevated amounts of both BIC RNA and miR-155 have been detected in clinical isolates of B cell lymphomas (5, 9–11), particularly those with the activated B cell (ABC) phenotype (9).
Generally, miRNAs decrease translation of the mRNAs to which they bind (2, 12). Because each cell type exhibits its own pattern of gene expression, it is not surprising that the amounts and identities of miRNAs present in cells are also tissue-specific and developmental stage–specific. Accumulation of mature miRNAs is determined by both the extent of synthesis of primary precursors of individual miRNAs (pri-miRNAs), such as BIC RNA, and the efficiency of the stepwise processing of these transcripts that generate the mature miRNAs (13). It is widely assumed that most or all of the changes in accumulation of particular miRNAs have functional consequences. However, it is possible that some changes in miRNA profiles are fortuitous and perhaps inconsequential results of events that are related to the response under study.
To learn about the control of miR-155 accumulation in innate immunity, Baltimore’s group (1) monitored the abundance of miR-155 and certain mRNAs in primary mouse bone marrow–derived macrophages after treatment with various TLR ligands or the cytokines tumor necrosis factor–{alpha} (TNF-{alpha}), interferon-beta (IFN-beta), and IFN-{gamma} (1). The authors observed that of ~200 miRNAs examined, only miR-155 increased in amount in response to both TLR ligands and IFN-beta. miR-155 accumulated upon treatment of macrophages with TLR ligands, such as double-stranded RNA [e.g., poly-r(I:C)] (which binds to TLR3), Gram-negative bacterial lipopolysaccharides (LPSs) (which bind to TLR4), the synthetic lipoprotein Pam3CSK4 (Pam3CysSerLys4; InvivoGen, San Diego, California) (which binds to TLR2), and unmethylated DNA (which binds to TLR9). Earlier work by this group showed that exposure of mouse monocytes to LPS leads to increased abundances of miR-132, miR-146, and miR-155 (14).
The specificities of the TLR responses were demonstrated by the fact that ligand-promoted increases in the amounts of miR-155 required the activities of the specific intermediate adaptor molecules MyD88 or TRIF, depending on the TLRs involved (1). For example, MyD88, which mediates the actions of TLR2 and TLR9, was necessary for stimulation by unmethylated DNA or Pam3CSK4, whereas TRIF, which serves as an adaptor for TLR3, was needed for a response to poly-r(I:C). Either adaptor sufficed for stimulation of miR-155 accumulation by LPS, as TLR4 can use either MyD88 or TRIF. The net result of these interactions was activation of the transcription factors NF-{kappa}B and AP-1, and synthesis of TNF-{alpha} mRNA.
TNF-{alpha} acts through an apparent autocrine pathway that requires TNF receptor–1 (TNFR1) activity to stimulate c-Jun N-terminal kinase (JNK) activity and hence to activate AP-1 (Fig. 1). Direct treatment of macrophages with TNF-{alpha} also promoted the accumulation of miR-155, but this factor appeared not to be required for the TLR-stimulated increase in miR-155 amounts. This response occurred even in cells derived from TNFR1–/– mice; hence, TLR signaling is likely to use an additional, more direct pathway to induce miR-155 accumulation.
As with the activation of TLRs, both IFN-beta and IFN-{gamma} increased the abundance of miR-155 and TNF-{alpha}. But in contrast to the TLR ligands, stimulation of miR-155 accumulation by IFN-beta appeared to require TNF-{alpha}, as it did not occur in cells lacking TNFR1. Moreover, the kinetics with which IFN treatment of macrophages led to an increase in miR-155 were slower than those for TLR ligands, consistent with an obligatory role of an intermediate such as TNF-{alpha}. Thus, although both ligand-bound TLRs and IFN-beta induce synthesis of TNF-{alpha}, only IFN-beta requires this factor for stimulation of miR-155 accumulation.
Inhibitor studies demonstrated that the increase in miR-155 stimulated by either pathway requires JNK activity, leading the authors to conclude that AP-1 is likely to be an essential activator of BIC gene transcription, at least during the inflammatory response. Consistent with this conclusion, Baltimore and colleagues noted that several AP-1 binding sites are present in the promoters of both mouse and human BIC genes. Putative NF-{kappa}B sites are present in the upstream region of the BIC promoter, and previous studies on the increased production of miR-155 in B cells have implicated NF-{kappa}B (15). This transcription factor also appears to support the increased accumulation of miR-146 in LPS-activated monocytes (14). The magnitudes of stimulation of the production of the miRNA described in these studies were not reported, so the relative impacts of stimulation by the various TLR ligands are difficult to assess.
An increase in the amount of BIC RNA present in stimulated macrophages supports the hypothesis that the accumulation of miR-155 is mediated via the regulation of transcription by the pathways described above. However, the amounts of miR-155 that accumulate may also be controlled through the regulation of the processing of BIC RNA. The efficiency of this processing can vary widely, as indicated by variation in the ratios of miR-155 to BIC RNA observed in various human lymphomas (9, 15). Controlled processing of other miRNA precursors is well documented as occurring in early embryonic development and in certain cancers (16, 17).
It is unclear what roles the increased amounts of miR-155 play in the macrophage inflammatory response (1). Despite the association between miR-155 abundance and several types of cancer (18, 19), few of its many potential mRNA targets have been authenticated experimentally (20, 21). Dozens of candidates have been identified by bioinformatics approaches (22), including the transcription regulatory proteins jumonji, PU.1, and CEBPbeta (9, 10).
Very recently, two studies showed that BIC RNA/miR-155 is needed for the establishment of a normal protective immune response; in the absence of miR-155, defects are observed in the production of a variety of cytokines that are known to contribute to immune system homeostasis and function (21, 23). Two good candidates (among many) identified in these studies as likely direct targets of miR-155 in this response are IL-10 and the transcription factor c-Maf.
Precise roles for miR-155 in supporting or terminating the development of an innate immune response in macrophages have yet to be demonstrated (24). miR-155 may act either to promote events that further inflammation or to inhibit or fine-tune the response, as has been proposed for miR-146 (14). The latter activity is crucial, of course, as failure to dampen the inflammation response could result in autoimmune diseases or toxic shock. If any miR-155 targets are regulated during the innate immune response, their identification will shed light on this important process.
Whatever the function of miR-155 in activated macrophages and monocytes, the known causative association between increased accumulation of miR-155 and the development of certain cancers makes it essential that cells keep this particular micromanager under tight control (1).
~undefinedCorresponding authors. E-mail, dahlberg@wisc.edu; elund@wisc.edu
References
1. R. M. O’Connell, K. D. Taganov, M. P. Boldin, G. Cheng, D. Baltimore, MicroRNA-155 is induced during the macrophage inflammatory response. Proc. Natl. Acad. Sci. U.S.A. 104, 1604–1609 (2007).[Abstract/Free Full Text]
2. D. P. Bartel, MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).[CrossRef][Medline]
3. W. P. Kloosterman, R. H. Plasterk, The diverse functions of microRNAs in animal development and disease. Dev. Cell 11, 441–450 (2006).[CrossRef][Medline]
4. R. Garzon, M. Fabbri, A. Cimmino, G. A. Calin, C. M. Croce, MicroRNA expression and function in cancer. Trends Mol. Med. 12, 580–587 (2006).[CrossRef][Medline]
5. W. Tam, J. E. Dahlberg, miR-155/BIC as an oncogenic microRNA. Genes Chromosomes Cancer 45, 211–212 (2006).[CrossRef][Medline]
6. M. T. McManus, MicroRNAs and cancer. Semin. Cancer Biol. 13, 253–258 (2003).[CrossRef][Medline]
7. W. Tam, S. H. Hughes, W. S. Hayward, P. Besmer, Avian bic, a gene isolated from a common retroviral site in avian leukosis virus-induced lymphomas that encodes a noncoding RNA, cooperates with c-myc in lymphomagenesis and erythroleukemogenesis. J. Virol. 76, 4275–4286 (2002).[Abstract/Free Full Text]
8. S. Costinean, N. Zanesi, Y. Pekarsky, E. Tili, S. Volinia, N. Heerema, C. M. Croce, Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 103, 7024–7029 (2006).[Abstract/Free Full Text]
9. P. S. Eis, W. Tam, L. Sun, A. Chadburn, Z. Li, M. F. Gomez, E. Lund, J. E. Dahlberg, Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc. Natl. Acad. Sci. U.S.A. 102, 3627–3632 (2005).[Abstract/Free Full Text]
10. J. Kluiver, S. Poppema, D. de Jong, T. Blokzijl, G. Harms, S. Jacobs, B. J. Kroesen, A. van den Berg, BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas. J. Pathol. 207, 243–249 (2005).[CrossRef][Medline]
11. M. Metzler, M. Wilda, K. Busch, S. Viehmann, A. Borkhardt, High expression of precursor microRNA-155/BIC RNA in children with Burkitt lymphoma. Genes Chromosomes Cancer 39, 167–169 (2004).[CrossRef][Medline]
12. R. J. Jackson, N. Standart, How do microRNAs regulate gene expression? Sci. STKE 2007, re1 (2007).[Abstract/Free Full Text]
13. V. N. Kim, MicroRNA biogenesis: Coordinated cropping and dicing. Nat. Rev. Mol. Cell Biol. 6, 376–385 (2005).[CrossRef][Medline]
14. K. D. Taganov, M. P. Boldin, K. J. Chang, D. Baltimore, NF-{kappa}B-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc. Natl. Acad. Sci. U.S.A. 103, 12481–12486 (2006).[Abstract/Free Full Text]
15. J. Kluiver, A. van den Berg, D. de Jong, T. Blokzijl, G. Harms, E. Bouwman, S. Jacobs, S. Poppema, B. J. Kroesen, Regulation of pri-microRNA BIC transcription and processing in Burkitt lymphoma. Oncogene 10.1038/sj.onc.1210147 (2006).
16. M. R. Suh, Y. Lee, J. Y. Kim, S. K. Kim, S. H. Moon, J. Y. Lee, K. Y. Cha, H. M. Chung, H. S. Yoon, S. Y. Moon, V. N. Kim, K. S. Kim, Human embryonic stem cells express a unique set of microRNAs. Dev. Biol. 270, 488–498 (2004).[CrossRef][Medline]
17. J. M. Thomson, M. Newman, J. S. Parker, E. M. Morin-Kensicki, T. Wright, S. M. Hammond, Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev. 20, 2202–2207 (2006).[Abstract/Free Full Text]
18. G. A. Calin, C. M. Croce, MicroRNA signatures in human cancers. Nat. Rev. Cancer 6, 857–866 (2006).[CrossRef][Medline]
19. S. Volinia, G. A. Calin, C. G. Liu, S. Ambs, A. Cimmino, F. Petrocca, R. Visone, M. Iorio, C. Roldo, M. Ferracin, R. L. Prueitt, N. Yanaihara, G. Lanza, A. Scarpa, A. Vecchione, M. Negrini, C. C. Harris, C. M. Croce, A microRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl. Acad. Sci. U.S.A. 103, 2257–2261 (2006).[Abstract/Free Full Text]
20. M. M. Martin, E. J. Lee, J. A. Buckenberger, T. D. Schmittgen, T. S. Elton, MicroRNA-155 regulates human angiotensin II type 1 receptor expression in fibroblasts. J. Biol. Chem. 281, 18277–18284 (2006).[Abstract/Free Full Text]
21. A. Rodriguez, E. Vigorito, S. Clare, M. V. Warren, P. Couttet, D. R. Sound, S. van Dongen, R. J. Grocock, P. P. Das, E. A. Miska, D. Vetrie, K. Okkenhaug, A. J. Enright, G. Dougan, M. Turner, A. Bardley, Requirement of bic/microRNA-155 for normal immune function. Science 316, 608–611 (2007).[Abstract/Free Full Text]
22. A. Krek, D. Grun, M. N. Poy, R. Wolf, L. Rosenberg, E. J. Epstein, P. MacMenamin, I. da Piedade, K. C. Gunsalus, M. Stoffel, N. Rajewsky, Combinatorial microRNA target predictions. Nat. Genet. 37, 495–500 (2005).[CrossRef][Medline]
23. T.-H. Thai, D. P. Calado, S. Casola, K. M. Ansel, C. Xiao, Y. Xue, A. Murphy, D. Frendewey, D. Valenzuela, J. L. Kutok, M. Schmidt-Supprian, N. Rajewsky, G. Yancopoulos, A. Rao, K. Rajewsky, Regulation of the germinal center response by microRNA-155. Science 316, 604–608 (2007).[Abstract/Free Full Text]
24. K. D. Taganov, M. P. Boldin, D. Baltimore, MicroRNAs and immunity: Tiny players in a big field. Immunity 26, 133–137 (2007).[CrossRef][Medline]
Fig. 1.
Multiple pathways in stimulated macrophages lead to increases in the amount of BIC RNA and hence miR-155. The binding of certain pathogen-associated molecules, such as the binding of double-stranded RNA to TLR3, leads to the activation of JNK and the transcription factor AP-1, which is likely a direct activator of transcription of the BIC locus. NF-{kappa}B may also be activated in this response. O’Connell et al. (1) demonstrated that ligands for TLR2, TLR4, and TLR9 also activated transcription of the BIC locus (not shown). Binding of IFN-beta to the IFN-{alpha}/beta receptor results in the synthesis and secretion of TNF-{alpha}, which signals through the TNF-{alpha} receptor in an autocrine fashion, leading to the activation of JNK. TLR activation also results in an increase in TNF-{alpha} production, but this is not essential for TLR-mediated production of miR-155. BIC RNA is processed by Drosha in the nucleus to produce pre–miR-155, which is then exported to the cytoplasm, where it is further processed by Dicer to produce mature miR-155.
Sci. STKE, 22 May 2007
Vol. 2007, Issue 387, p. pe25
Micromanagement During the Innate Immune Response
Innate immunity, a well-studied physiological response to bacterial, viral, and other pathogens, is of crucial importance to the survival of organisms as different as humans and flies. The innate immune response is initiated by the binding of a large array of ligands to membrane-associated pathogen recognition receptor proteins known as Toll-like receptors (TLRs), or by treatment with certain cytokines. Recent microarray studies have shown that one consequence of activation of mouse macrophages is an increased accumulation of one or a few microRNAs (miRNAs), specifically miR-155 (1).
miRNAs are small (~22 nucleotides) yet powerful regulators of gene expression that function primarily by reducing the abilities of specific mRNAs to direct the synthesis of their encoded proteins (2). The abundances of particular miRNAs in cells are subject to change in response to physiological stimuli, thereby supporting the normal progression through sequential stages of development or the maintenance of homeostasis (3). However, accumulation of inappropriate amounts of a miRNA can lead to pathologies, notably cancer (4).
One of the first miRNAs associated with cancer was miR-155 [summarized in ( 5)]. This "onco-miRNA" is processed from the third exon of BIC (B cell integration cluster) RNA, which was originally identified as a spliced and polyadenylated but noncoding RNA (ncRNA), ~1700 nucleotides long, accumulating in certain chicken B cell lymphomas. In lymphomas that developed upon infection with avian leukosis virus (ALV), synthesis of BIC RNA was directed by transcription from the integrated ALV provirus into the adjacent cellular BIC gene.
Although it was initially unclear how a large ncRNA affected the development of cancer, a phylogenetically conserved structured region was proposed to be important (5); this region was later found to encode miR-155 ( 6 ), which has a direct role in cancer. Initially, Tam and colleagues (7) showed that expression of the region of BIC RNA containing the hairpin precursor of miR-155 accelerates formation of myc-dependent lymphomas in chickens. More recently, Croce and collaborators ( 8 ) reported that overexpression of miR-155 in pre-B cells of transgenic mice greatly promotes the development of B cell malignancies. The BIC gene has its own promoter, and elevated amounts of both BIC RNA and miR-155 have been detected in clinical isolates of B cell lymphomas (5, 9–11), particularly those with the activated B cell (ABC) phenotype (9).
Generally, miRNAs decrease translation of the mRNAs to which they bind (2, 12). Because each cell type exhibits its own pattern of gene expression, it is not surprising that the amounts and identities of miRNAs present in cells are also tissue-specific and developmental stage–specific. Accumulation of mature miRNAs is determined by both the extent of synthesis of primary precursors of individual miRNAs (pri-miRNAs), such as BIC RNA, and the efficiency of the stepwise processing of these transcripts that generate the mature miRNAs (13). It is widely assumed that most or all of the changes in accumulation of particular miRNAs have functional consequences. However, it is possible that some changes in miRNA profiles are fortuitous and perhaps inconsequential results of events that are related to the response under study.
To learn about the control of miR-155 accumulation in innate immunity, Baltimore’s group (1) monitored the abundance of miR-155 and certain mRNAs in primary mouse bone marrow–derived macrophages after treatment with various TLR ligands or the cytokines tumor necrosis factor–{alpha} (TNF-{alpha}), interferon-beta (IFN-beta), and IFN-{gamma} (1). The authors observed that of ~200 miRNAs examined, only miR-155 increased in amount in response to both TLR ligands and IFN-beta. miR-155 accumulated upon treatment of macrophages with TLR ligands, such as double-stranded RNA [e.g., poly-r(I:C)] (which binds to TLR3), Gram-negative bacterial lipopolysaccharides (LPSs) (which bind to TLR4), the synthetic lipoprotein Pam3CSK4 (Pam3CysSerLys4; InvivoGen, San Diego, California) (which binds to TLR2), and unmethylated DNA (which binds to TLR9). Earlier work by this group showed that exposure of mouse monocytes to LPS leads to increased abundances of miR-132, miR-146, and miR-155 (14).
The specificities of the TLR responses were demonstrated by the fact that ligand-promoted increases in the amounts of miR-155 required the activities of the specific intermediate adaptor molecules MyD88 or TRIF, depending on the TLRs involved (1). For example, MyD88, which mediates the actions of TLR2 and TLR9, was necessary for stimulation by unmethylated DNA or Pam3CSK4, whereas TRIF, which serves as an adaptor for TLR3, was needed for a response to poly-r(I:C). Either adaptor sufficed for stimulation of miR-155 accumulation by LPS, as TLR4 can use either MyD88 or TRIF. The net result of these interactions was activation of the transcription factors NF-{kappa}B and AP-1, and synthesis of TNF-{alpha} mRNA.
TNF-{alpha} acts through an apparent autocrine pathway that requires TNF receptor–1 (TNFR1) activity to stimulate c-Jun N-terminal kinase (JNK) activity and hence to activate AP-1 (Fig. 1). Direct treatment of macrophages with TNF-{alpha} also promoted the accumulation of miR-155, but this factor appeared not to be required for the TLR-stimulated increase in miR-155 amounts. This response occurred even in cells derived from TNFR1–/– mice; hence, TLR signaling is likely to use an additional, more direct pathway to induce miR-155 accumulation.
As with the activation of TLRs, both IFN-beta and IFN-{gamma} increased the abundance of miR-155 and TNF-{alpha}. But in contrast to the TLR ligands, stimulation of miR-155 accumulation by IFN-beta appeared to require TNF-{alpha}, as it did not occur in cells lacking TNFR1. Moreover, the kinetics with which IFN treatment of macrophages led to an increase in miR-155 were slower than those for TLR ligands, consistent with an obligatory role of an intermediate such as TNF-{alpha}. Thus, although both ligand-bound TLRs and IFN-beta induce synthesis of TNF-{alpha}, only IFN-beta requires this factor for stimulation of miR-155 accumulation.
Inhibitor studies demonstrated that the increase in miR-155 stimulated by either pathway requires JNK activity, leading the authors to conclude that AP-1 is likely to be an essential activator of BIC gene transcription, at least during the inflammatory response. Consistent with this conclusion, Baltimore and colleagues noted that several AP-1 binding sites are present in the promoters of both mouse and human BIC genes. Putative NF-{kappa}B sites are present in the upstream region of the BIC promoter, and previous studies on the increased production of miR-155 in B cells have implicated NF-{kappa}B (15). This transcription factor also appears to support the increased accumulation of miR-146 in LPS-activated monocytes (14). The magnitudes of stimulation of the production of the miRNA described in these studies were not reported, so the relative impacts of stimulation by the various TLR ligands are difficult to assess.
An increase in the amount of BIC RNA present in stimulated macrophages supports the hypothesis that the accumulation of miR-155 is mediated via the regulation of transcription by the pathways described above. However, the amounts of miR-155 that accumulate may also be controlled through the regulation of the processing of BIC RNA. The efficiency of this processing can vary widely, as indicated by variation in the ratios of miR-155 to BIC RNA observed in various human lymphomas (9, 15). Controlled processing of other miRNA precursors is well documented as occurring in early embryonic development and in certain cancers (16, 17).
It is unclear what roles the increased amounts of miR-155 play in the macrophage inflammatory response (1). Despite the association between miR-155 abundance and several types of cancer (18, 19), few of its many potential mRNA targets have been authenticated experimentally (20, 21). Dozens of candidates have been identified by bioinformatics approaches (22), including the transcription regulatory proteins jumonji, PU.1, and CEBPbeta (9, 10).
Very recently, two studies showed that BIC RNA/miR-155 is needed for the establishment of a normal protective immune response; in the absence of miR-155, defects are observed in the production of a variety of cytokines that are known to contribute to immune system homeostasis and function (21, 23). Two good candidates (among many) identified in these studies as likely direct targets of miR-155 in this response are IL-10 and the transcription factor c-Maf.
Precise roles for miR-155 in supporting or terminating the development of an innate immune response in macrophages have yet to be demonstrated (24). miR-155 may act either to promote events that further inflammation or to inhibit or fine-tune the response, as has been proposed for miR-146 (14). The latter activity is crucial, of course, as failure to dampen the inflammation response could result in autoimmune diseases or toxic shock. If any miR-155 targets are regulated during the innate immune response, their identification will shed light on this important process.
Whatever the function of miR-155 in activated macrophages and monocytes, the known causative association between increased accumulation of miR-155 and the development of certain cancers makes it essential that cells keep this particular micromanager under tight control (1).
~undefinedCorresponding authors. E-mail, dahlberg@wisc.edu; elund@wisc.edu
References
1. R. M. O’Connell, K. D. Taganov, M. P. Boldin, G. Cheng, D. Baltimore, MicroRNA-155 is induced during the macrophage inflammatory response. Proc. Natl. Acad. Sci. U.S.A. 104, 1604–1609 (2007).[Abstract/Free Full Text]
2. D. P. Bartel, MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).[CrossRef][Medline]
3. W. P. Kloosterman, R. H. Plasterk, The diverse functions of microRNAs in animal development and disease. Dev. Cell 11, 441–450 (2006).[CrossRef][Medline]
4. R. Garzon, M. Fabbri, A. Cimmino, G. A. Calin, C. M. Croce, MicroRNA expression and function in cancer. Trends Mol. Med. 12, 580–587 (2006).[CrossRef][Medline]
5. W. Tam, J. E. Dahlberg, miR-155/BIC as an oncogenic microRNA. Genes Chromosomes Cancer 45, 211–212 (2006).[CrossRef][Medline]
6. M. T. McManus, MicroRNAs and cancer. Semin. Cancer Biol. 13, 253–258 (2003).[CrossRef][Medline]
7. W. Tam, S. H. Hughes, W. S. Hayward, P. Besmer, Avian bic, a gene isolated from a common retroviral site in avian leukosis virus-induced lymphomas that encodes a noncoding RNA, cooperates with c-myc in lymphomagenesis and erythroleukemogenesis. J. Virol. 76, 4275–4286 (2002).[Abstract/Free Full Text]
8. S. Costinean, N. Zanesi, Y. Pekarsky, E. Tili, S. Volinia, N. Heerema, C. M. Croce, Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 103, 7024–7029 (2006).[Abstract/Free Full Text]
9. P. S. Eis, W. Tam, L. Sun, A. Chadburn, Z. Li, M. F. Gomez, E. Lund, J. E. Dahlberg, Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc. Natl. Acad. Sci. U.S.A. 102, 3627–3632 (2005).[Abstract/Free Full Text]
10. J. Kluiver, S. Poppema, D. de Jong, T. Blokzijl, G. Harms, S. Jacobs, B. J. Kroesen, A. van den Berg, BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas. J. Pathol. 207, 243–249 (2005).[CrossRef][Medline]
11. M. Metzler, M. Wilda, K. Busch, S. Viehmann, A. Borkhardt, High expression of precursor microRNA-155/BIC RNA in children with Burkitt lymphoma. Genes Chromosomes Cancer 39, 167–169 (2004).[CrossRef][Medline]
12. R. J. Jackson, N. Standart, How do microRNAs regulate gene expression? Sci. STKE 2007, re1 (2007).[Abstract/Free Full Text]
13. V. N. Kim, MicroRNA biogenesis: Coordinated cropping and dicing. Nat. Rev. Mol. Cell Biol. 6, 376–385 (2005).[CrossRef][Medline]
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Fig. 1.
Multiple pathways in stimulated macrophages lead to increases in the amount of BIC RNA and hence miR-155. The binding of certain pathogen-associated molecules, such as the binding of double-stranded RNA to TLR3, leads to the activation of JNK and the transcription factor AP-1, which is likely a direct activator of transcription of the BIC locus. NF-{kappa}B may also be activated in this response. O’Connell et al. (1) demonstrated that ligands for TLR2, TLR4, and TLR9 also activated transcription of the BIC locus (not shown). Binding of IFN-beta to the IFN-{alpha}/beta receptor results in the synthesis and secretion of TNF-{alpha}, which signals through the TNF-{alpha} receptor in an autocrine fashion, leading to the activation of JNK. TLR activation also results in an increase in TNF-{alpha} production, but this is not essential for TLR-mediated production of miR-155. BIC RNA is processed by Drosha in the nucleus to produce pre–miR-155, which is then exported to the cytoplasm, where it is further processed by Dicer to produce mature miR-155.
http://bloodjournal.hematologylibrary.org/cgi/content/full/113/20/4914
http://jem.rupress.org/cgi/content/full/205/3/585
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
miR-155 gene: A typical multifunctional microRNA
Volume 1792, Issue 6, June 2009, Pages 497-505
http://jem.rupress.org/cgi/content/full/205/3/585
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
miR-155 gene: A typical multifunctional microRNA
Volume 1792, Issue 6, June 2009, Pages 497-505
非常感谢版主给予的极好的文章及中肯的建议，恩，我得认真阅读第二篇文章，涉及通路就觉得难，再请教！
再次感谢版主！
再次感谢版主！
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