Abstract
Cellular information processing requires the coordinated activity of a large network of intracellular signalling pathways. Cross-talk between pathways provides for complex non-linear responses to combinations of stimuli, but little is known about the density of these interactions in any specific cell. Here, we have analysed a large-scale survey of pathway interactions carried out by the Alliance for Cellular Signalling (AfCS) in RAW 264.7 macrophages. Twenty-two receptor-specific ligands were studied, both alone and in all pairwise combinations, for Ca2+ mobilization, cAMP synthesis, phosphorylation of many signalling proteins and for cytokine production. A large number of non-additive interactions are evident that are consistent with known mechanisms of cross-talk between pathways, but many novel interactions are also revealed. A global analysis of cross-talk suggests that many external stimuli converge on a relatively small number of interaction mechanisms to provide for context-dependent signalling.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Gilman, A. G. et al. Overview of the Alliance for Cellular Signaling. Nature 420, 703–706 (2002).
Akira, S., Yamamoto, M. & Takeda, K. Role of adapters in Toll-like receptor signalling. Biochem. Soc. Trans. 31, 637–642 (2003).
Ihle, J. N. Cytokine receptor signalling. Nature 377, 591–594 (1995).
Chen, Z. P., Levy, A. & Lightman, S. L. Nucleotides as extracellular signalling molecules. J. Neuroendocrinol. 7, 83–96 (1995).
Chen, L. W., Lin, M. W. & Hsu, C. M. Different pathways leading to activation of extracellular signal-regulated kinase and p38 MAP kinase by formyl-methionyl-leucyl-phenylalanine or platelet activating factor in human neutrophils. J. Biomed. Sci. 12, 311–319 (2005).
Sato, S. et al. Synergy and cross-tolerance between toll-like receptor (TLR) 2- and TLR4-mediated signaling pathways. J. Immunol. 165, 7096–7101 (2000).
Medvedev, A. E., Kopydlowski, K. M. & Vogel, S. N. Inhibition of lipopolysaccharide-induced signal transduction in endotoxin-tolerized mouse macrophages: dysregulation of cytokine, chemokine, and toll-like receptor 2 and 4 gene expression. J. Immunol. 164, 5564–5574 (2000).
Hemmi, H. et al. The roles of two IκB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J. Exp. Med. 199, 1641–1650 (2004).
Hausler, K. G. et al. InterferonK differentially modulates the release of cytokines and chemokines in lipopolysaccharide- and pneumococcal cell wall-stimulated mouse microglia and macrophages. Eur. J. Neurosci. 16, 2113–2122 (2002).
Yamamoto, M. et al. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-β promoter in the Toll-like receptor signaling. J. Immunol. 169, 6668–6672 (2002).
Gessani, S., Belardelli, F., Pecorelli, A., Puddu, P. & Baglioni, C. Bacterial lipopolysaccharide and γ-interferon induce transcription of β-interferon mRNA and interferon secretion in murine macrophages. J. Virol. 63, 2785–2789 (1989).
Tilg, H. & Kaser, A. Type I interferons and their therapeutic role in Th2-regulated inflammatory disorders. Expert Opin. Biol. Ther. 4, 469–481 (2004).
Aderka, D., Le, J. & Vilcek, J. IL-6 inhibits lipopolysaccharide-induced tumor necrosis factor production in cultured human monocytes, U937 cells, and in mice. J. Immunol. 143, 3517–3523 (1989).
Heeg, K. & Dalpke, A. TLR-induced negative regulatory circuits: role of suppressor of cytokine signaling (SOCS) proteins in innate immunity. Vaccine 21, S61–S67 (2003).
Niemand, C. et al. Activation of STAT3 by IL-6 and IL-10 in primary human macrophages is differentially modulated by suppressor of cytokine signaling 3. J. Immunol. 170, 3263–3272 (2003).
Zhang, H. et al. Effect of adrenoreceptors on endotoxin-induced cytokines and lipid peroxidation in lung explants. Am. J. Respir. Crit. Care Med. 160, 1703–1710 (1999).
Lukashev, D., Ohta, A., Apasov, S., Chen, J. F. & Sitkovsky, M. Cutting edge: Physiologic attenuation of proinflammatory transcription by the Gs protein-coupled A2A adenosine receptor in vivo. J. Immunol. 173, 21–24 (2004).
O'Donnell, P. M. & Taffet, S. M. The proximal promoter region is essential for lipopolysaccharide induction and cyclic AMP inhibition of mouse tumor necrosis factor-α. J. Interferon Cytokine Res. 22, 539–548 (2002).
Hareng, L., Meergans, T., von Aulock, S., Volk, H. D. & Hartung, T. Cyclic AMP increases endogenous granulocyte colony-stimulating factor formation in monocytes and THP-1 macrophages despite attenuated TNF-α formation. Eur. J. Immunol. 33, 2287–2296 (2003).
Akaogi, J. et al. Prostaglandin E2 receptors EP2 and EP4 are up-regulated in peritoneal macrophages and joints of pristane-treated mice and modulate TNF-α and IL-6 production. J. Leukoc. Biol. 76, 227–236 (2004).
Farmer, P. & Pugin, J. β-adrenergic agonists exert their 'anti-inflammatory' effects in monocytic cells through the IκB/NF-κB pathway. Am. J. Physiol. Lung Cell Mol. Physiol. 279, L675–L682 (2000).
Nansen, A. & Randrup Thomsen, A. Viral infection causes rapid sensitization to lipopolysaccharide: central role of IFN-αβ. J. Immunol. 166, 982–988 (2001).
Durbin, J. et al. The role of STAT1 in viral sensitization to LPS. J. Endotoxin. Res. 9, 313–316 (2003).
Hertzog, P. J., O'Neill, L. A. & Hamilton, J. A. The interferon in TLR signaling: more than just antiviral. Trends Immunol. 24, 534–539 (2003).
Harada, K., Isse, K. & Nakanuma, Y. Interferon gamma accelerates NF-κB activation of biliary epithelial cells induced by Toll-like receptor and ligand interaction. J. Clin. Pathol. 59, 184–190 (2006).
Zhao, J. et al. IRF-8/ICSBP is involved in TLR signaling and contributes to the cross talk between TLR and IFN-γ signaling pathways. J. Biol. Chem. 281, 10073–10080 (2006).
Baetz, A., Frey, M., Heeg, K. & Dalpke, A. H. Suppressor of cytokine signaling (SOCS) proteins indirectly regulate toll-like receptor signaling in innate immune cells. J. Biol. Chem. 279, 54708–54715 (2004).
Dalpke, A. H. & Heeg, K. Synergistic and antagonistic interactions between LPS and superantigens. J. Endotoxin Res. 9, 51–54 (2003).
Vandeusen, J. B. et al. STAT-1-mediated repression of monocyte interleukin-10 gene expression in vivo. Eur. J. Immunol. 36, 623–630 (2006).
Mojena, R. Hierarchical grouping methods and stopping rules: An evaluation. Computer J. 20, 359–363 (1977).
Rozen, S. & Skaletsky, H. Primer3 on the WWW for general users and for biologist programmers. Methods Mol. Biol. 132, 365–386 (2000).
Acknowledgements
We are indebted to the many individuals from several academic institutes that are members of the AfCS scientific team for data collection, for database construction and for providing general help and advice. this work would not have been possible without the transparent and efficient public access to raw experimental data supported by the AfCS effort. We also thank members of the AfCS steering committee and the Ranganathan lab for discussion and critical reading of the manuscript. Work on this project was supported by contributions from public and private sources, including the NIGMS Glue Grant Initiative (U54 GM062114). A complete listing of the AfCS sponsors can be found at http://www.signalling-gateway.org/aboutus/sponsors.html. R.R. acknowledges support from the Mallinckrodt Scholar award, the Keck Future Initiatives award and the Robert A. Welch Foundation, and is an investigator of the Howard Hughes Medical Institute. P.C.S. acknowledges support from the Robert A. Welch Foundation and is the Alfred and Mabel Gilman Chair in molecular pharmacology.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Information
Supplementary Figures S1, S2, S3, S4, Supplementary Tables S1, S2, Supplementary Methods and Supplementary References (PDF 1397 kb)
Rights and permissions
About this article
Cite this article
Natarajan, M., Lin, KM., Hsueh, R. et al. A global analysis of cross-talk in a mammalian cellular signalling network. Nat Cell Biol 8, 571–580 (2006). https://doi.org/10.1038/ncb1418
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ncb1418
This article is cited by
-
Synthetic extracellular matrices with function-encoding peptides
Nature Reviews Bioengineering (2023)
-
Expression correlation attenuates within and between key signaling pathways in chronic kidney disease
BMC Medical Genomics (2020)
-
In the Light of the Environment: Evolution Through Biogrammars Not Programmers
Biological Theory (2020)
-
Integrating data and knowledge to identify functional modules of genes: a multilayer approach
BMC Bioinformatics (2019)
-
Pathological cardiac hypertrophy: the synergy of adenylyl cyclases inhibition in cardiac and immune cells during chronic catecholamine stress
Journal of Molecular Medicine (2019)