TLR4 Mediates Pneumolysin-Induced ATF3 Expression through the JNK/p38 Pathway in Streptococcus pneumoniae-Infected RAW 264.7 Cells

다국어 초록 (Multilingual Abstract)

Activating transcription factor-3 (ATF3) acts as a negative regulator of cytokine production during Gram-negative bacterial infection. A recent study reported that ATF3 provides protection from Streptococcus pneumoniae infection by activating cytokines. However, the mechanism by which S.
pneumoniae induces ATF3 after infection is still unknown. In this study, we show that ATF3 was upregulated via Toll-like receptor (TLR) pathways in response to S. pneumoniae infection in vitro. Induction was mediated by TLR4 and TLR2, which are in the TLR family. The expression of ATF3 was induced by pneumolysin (PLY), a potent pneumococcal virulence factor, via the TLR4 pathway. Furthermore, ATF3 induction is mediated by p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). Thus, this study reveals a potential role of PLY in modulating ATF3 expression, which is required for the regulation of immune responses against pneumococcal infection in macrophages.

참고문헌 (Reference)

1 Kenzel, S., "c-Jun kinase is a critical signaling molecule in a neonatal model of group B streptococcal sepsis" 176 : 3181-3188, 2006

2 Kallunki, T., "c-Jun can recruit JNK to phosphorylate dimerization partners via specific docking interactions" 87 : 929-939, 1996

3 Calton, C. M., "Upregulation of ATF3inhibits expression of the pro-inflammatory cytokine IL-6 during Neisseria gonorrhoeae infection" 15 : 1837-1850, 2013

4 Basset, A., "Toll-like receptor(TLR)2 mediates inflammatory responses to oligomerized RrgA pneumococcal pilus type 1 protein" 288 : 2665-2675, 2012

5 Lu, D., "The regulation of ATF3 gene expression by mitogen-activated protein kinases" 401 : 559-567, 2007

6 Hyams, C., "The Streptococcus pneumoniae capsule inhibits complement activity and neutrophil phagocytosis by multiple mechanisms" 78 : 704-715, 2010

7 Gilchrist, M., "Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4" 441 : 173-178, 2006

8 N’Guessan, P. D., "Streptococcus pneumoniae induced p38 MAPK-and NF-kB-dependent COX-2 expression in human lung epithelium" 290 : 1131-1138, 2006

9 Schmeck, B., "Streptococcus pneumoniae induced c-Jun-N-terminal kinaseand AP-1-dependent IL-8 release by lung epithelial BEAS-2B cells" 7 : 98-, 2006

10 File, Jr. T. M., "Streptococcus pneumoniae and communityacquired pneumonia : a cause for concern" 117 : 39-50, 2004

11 Nguyen, C. T., "S. pneumoniae ClpL modulates adherence to A549 human lung cells through Rap1/Rac1 activation" 82 : 3802-3810, 2014

12 Dessing, M. C., "Role played by Toll-like receptors 2and 4 in lipoteichoic acid-induced lung inflammation and coagulation" 197 : 245-252, 2008

13 Malley, R., "Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection" 100 : 1966-1971, 2003

14 Koppe, U., "Recognition of Streptococcus pneumoniae by the innate immune system" 14 : 460-466, 2012

15 Hoetzenecker, W., "ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression" 18 : 128-134, 2012

16 McNeela, E. A., "Pneumolysin activates the NLRP3inflammasome and promotes proinflammatory cytokines independently of TLR4" 6 : 1001191-, 2010

17 Tu, L. N., "Modulation of adherence, invasion, and tumor necrosis factor alpha secretion during the early stages of infection by Streptococcus pneumoniae ClpL" 75 : 2996-3005, 2007

18 Schröder, N. W. J., "Lipoteichoic acid(LTA)of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor(TLR)-2, lipopolysaccharide-binding protein(LBP), and CD14, whereas TLR-4 and MD-2 are not involved" 278 : 15587-15594, 2003

19 Choi, I. H., "Limited stress response in Streptococcus pneumoniae" 43 : 807-812, 1999

20 Li, L., "JNK-dependent phosphorylation of c-Jun on serine 63 mediates nitric oxide-induced apoptosis of neuroblastoma cells" 279 : 4058-4065, 2004

21 Aung, H. H., "Induction of ATF3 gene network by triglyceride-rich lipoprotein lipolysis products increases vascular apoptosis and inflammation" 33 : 2088-2096, 2013

22 Kabelitz, D., "Expression and function of Toll-like receptors in T lymphocytes" 19 : 39-45, 2007

23 Kang, E. H., "EstA protein, a novel virulence factor of Streptococcus pneumoniae, induces nitric oxide and pro-inflammatory cytokine production in RAW 264. 7 macrophages through NF-kB/MAPK" 47 : 196-201, 2009

24 Wartha, F., "Capsule and dalanylated lipoteichoic acids protect Streptococcus pneumoniae against neutrophil extracellular traps" 9 : 1162-1171, 2007

25 Khuu, C. H., "Activating transcription factor 3(ATF3)represses the expression of CCL4 in murine macrophages" 44 : 1598-1605, 2007

26 Filén, S., "Activating transcription factor 3 is a positive regulator of human IFNG gene expression" 184 : 4990-4999, 2010

27 Gilchrist, M., "Activating transcription factor 3 is a negative regulator of allergic pulmonary inflammation" 205 : 2349-2357, 2008

28 Thompson, M., "ATF3 transcription factor and its emerging roles in immunity and cancer" 87 : 1053-1060, 2009

29 Rosenberger, C. M., "ATF3 regulates MCMV infection in mice by modulating IFN-gamma expression in natural killer cells" 105 : 2544-2549, 2008

30 Lai, P. -F., "ATF3 protects against LPS-induced inflammation in mice via inhibiting HMGB1 expression" 2013 : 716481-, 2013

31 Boespflug, N. D., "ATF3 is a novel regulator of mouse neutrophil migration" 123 : 2084-2093, 2014

32 Nguyen, C. T., "ATF3 confers resistance to pneumococcal infection through positive regulation of cytokine production" 210 : 1745-1754, 2014

33 Hai, T., "ATF3 and stress responses" 7 : 321-335, 1999

34 Benton, K. A., "A pneumolysinnegative mutant of Streptococcus pneumoniae causes chronic bacteremia rather than acute sepsis in mice" 63 : 448-455, 1995

35 Gilchrist, M., "A key role for ATF3 in regulating mast cell survival and mediator release" 115 : 4734-4741, 2010