Abstract
Inflammation involves the sequential activation of signaling pathways leading to the production of both pro- and anti-inflammatory mediators. Although much attention has focused on pro-inflammatory pathways that initiate inflammation, relatively little is known about the mechanisms that switch off inflammation and resolve the inflammatory response. The transcription factor NF-κB is thought to have a central role in the induction of pro-inflammatory gene expression and has attracted interest as a new target for the treatment of inflammatory disease. We show here that NF-κB activation in leukocytes recruited during the onset of inflammation is associated with pro-inflammatory gene expression, whereas such activation during the resolution of inflammation is associated with the expression of anti-inflammatory genes and the induction of apoptosis. Inhibition of NF-κB during the resolution of inflammation protracts the inflammatory response and prevents apoptosis. This suggests that NF-κB has an anti-inflammatory role in vivo involving the regulation of inflammatory resolution.
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References
Gilroy, D.W. et al. Inducible cyclooxygenase may have anti-inflammatory properties. Nature Med. 5, 698–701 (1999).
Levy, B.D., Clish, C.B., Schmidt, B., Gronert, K. & Serhan, C.N. Lipid mediator class switching during acute inflammation: signals in resolution. Nature Immunol. 2, 612–619 (2001).
Savill, J. Apoptosis in resolution of inflammation. J. Leukoc. Biol. 61, 375–380 (1997).
Haslett, C. Granulocyte apoptosis and inflammatory disease. Br. Med. Bull. 53, 669–683 (1997).
Karin, M. & Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Ann. Rev. Immunol. 18, 621–663 (2000).
Vane, J.R. et al. Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc. Natl. Acad. Sci. U.S.A. 91, 2046–2050 (1994).
Tomlinson, A. & Willoughby, D.A. Inducible enzymes in inflammation: advances, interactions and conflict. Inducible Enzymes in the Inflammatory Response (eds Tomlinson, A. & Willoughby, D.A.) 187–207 (Birkhäuser, Basel, Switzerland, 1999).
Tak, P.P. & Firestein, G.S. NF-κB : a key role in inflammatory diseases. J. Clin. Invest. 107, 7–11 (2001).
Yamamoto, Y. & Gaynor, R.B. Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer. J. Clin. Invest. 107, 135–142 (2001).
Hobbs, A.J. & Moncada, S. Inducible nitric oxide synthase and inflammation. Inducible Enzymes in the Inflammatory Response (eds Tomlinson, A. & Willoughby, D.A.) 31–55 (Birkhäuser, Basel, Switzerland, 1999).
Alcamo, E. et al. Targeted mutation of TNF-receptor I rescues the RelA-deficient mouse and reveals a critical role for NF-κB in leukocyte recruitment. J. Immunol. 167, 1592–1600 (2001).
Grigoriadis, G. et al. The Rel subunit of NF-κB–like transcription factor is a positive and negative regulator of macrophage gene expression: distinct roles for Rel in different macrophage populations. EMBO J. 15, 7099–7170 (1996).
Carrasco, D. et al. Multiple hemopoietic defects and lymphoid hyperplasia in mice lacking the transcriptional activation domain of the c-Rel protein. J. Exp. Med. 187, 973–984 (1998).
Grossmann, M. et al. The combined absence of the transcription factors Rel and RelA leads to multiple hemopoietic cell defects. Proc. Natl. Acad. Sci. USA 96, 11848–11853 (1999).
Bohuslav, J. et al. Regulation of an essential innate immune response by the p50 subunit of NF-κB. J. Clin. Invest. 102, 1645–1652 (1998).
Ishikawa, H. et al. Chronic inflammation and susceptibility to bacterial infections in mice lacking the polypeptide (p)105 precursor ( NF-κB1) but expressing p50. J. Exp. Med. 187, 985–996 (1998).
Tomlinson, A. et al. Cyclo-oxygenase and nitric oxide synthase isoforms in rat carrageenin-induced pleurisy. Brit. J. Pharm. 113, 693–698 (1994).
Xie, Q.W., Kashiwabara, Y. & Nathan, C. Role of transcription factor NF-κB/Rel in induction of nitric oxide synthase. J. Biol. Chem. 269, 4705–8 (1994).
Salmerón, A. et al. Direct phosphorylation of NF-κB1 p105 by the IκB kinase complex on serine 927 is essential for signal-induced p105 proteolysis. J. Biol. Chem. 276, 22215–22222 (2001).
Rossi, A. et al. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase. Nature 403, 103–108 (2000).
Straus, D.S. et al. 15-deoxy-δ12,14-prostaglandin J2 inhibits multiple steps in the NF-κB signaling pathway. Proc. Natl. Acad. Sci. U.S.A. 97, 4844–4849 (2000).
Castrillo, A., Diaz-Guerra, M.J., Hortelano, S., Martin-Sanz, P. & Bosca, L. Inhibition of IκB kinase and IκB phosphorylation by 15-deoxy-δ(12,14)-prostaglandin J(2) in activated murine macrophages. Mol. Cell. Biol. 20, 1692–1698 (2000).
Senftleben, U. et al. Activation of a second, evolutionarily conserved, NF-κB signaling pathway. Science 293, 1495–1499 (2001).
Bours, V. et al. The oncoprotein Bcl-3 directly transactivates through κB motifs via association with DNA-binding p50B homodimers. Cell 72, 729–739 (1993).
Fujita, T., Nolan, G.P., Liou, H.C., Scott, M.L. & Baltimore, D. The candidate proto-oncogene bcl-3 encodes a transcriptional coactivator that activates through NF-κB p50 homodimers. Genes Dev. 7, 1354–1363 (1993).
Thomas, B. et al. Critical role of C/EBPδ and C/EBPβ factors in the stimulation of the cyclooxygenase-2 gene transcription by interleukin-1β in articular chondrocytes. Eur. J. Biochem. 267, 6798–6809 (2000).
Wadleigh, D.J., Reddy, S.T., Kopp, E., Ghosh, S. & Herschman, H.R. Transcriptional activation of the cyclooxygenase-2 gene in endotoxin-treated RAW 264.7 macrophages. J. Biol. Chem. 275, 6259–6266 (2000).
Liu, S.F., Ye, X. & Malik, A.B. Inhibition of NF-κB activation by pyrrolidine dithiocarbamate prevents in vivo expression of proinflammatory genes. Circulation 100, 1330–1337 (1999).
Pierce, J.W. et al. Novel inhibitors of cytokine-induced IκBα phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo. J. Biol. Chem. 272, 21096–21103 (1997).
Miagkov, A.V. et al. NF-κB activation provides the potential link between inflammation and hyperplasia in the arthritic joint. Proc. Natl. Acad. Sci. U.S.A. 95, 13859–13864 (1998).
Lin, B. et al. NF-κB functions as both a proapoptotic and antiapoptotic regulatory factor within a single cell type. Cell Death Differ. 6, 570–582 (1999).
Yin, C., Knudson, M., Korsmeyer, S.J. & Van Dyke, T. Bax suppresses tumorigenesis and stimulates apoptosis in vivo. Nature 385, 637–640 (1997).
Lotem, J. & Sachs, L. Cytokine suppression of protease activation in wild-type p53-dependent and p53-independent apoptosis. Proc. Natl. Acad. Sci. USA 94, 9349–9353 (1997).
Dibbert, B. et al. Cytokine-mediated bax deficiency and consequent delayed neutrophil apoptosis: A general mechanism to accumulate effector cells in inflammation. Proc. Natl. Acad. Sci. USA 96, 13330–13335 (1999).
Xaus, J. et al.. LPS induces apoptosis in macrophages mostly through the autocrine production of TNF-α. Blood 95, 3823–3831 (2000).
Li, Z-W. et al. The IKKβ subunit of IκB kinase (IKK) is essential for nuclear factor κB activation and prevention of apoptosis. J. Exp. Med. 189, 1839–1845 (1999).
Igata, E. et al. Molecular cloning and functional analysis of the murine bax gene promoter. Gene 238, 407–415 (1999).
Wu, H. & Lozano, G. NF-κB activation of p53. J. Biol. Chem. 269, 20067–20074 (1994).
Sun, X., Shimizu, H. & Yamamoto, K-I. Identification of a novel p53 promoter element involved in genotoxic stress–inducible p53 expression. Mol. Cell Biol. 15, 4489–4496 (1995).
Kirch, H.-C., Flaswinkel, S., Rumpf, H., Brockmann, D. & Esche, H. Expression of human p53 requires synergistic activation of transcription from the p53 promoter by AP-1, NF-κB and Myc/Max. Oncogene 18, 2728–2738 (1999).
Fadok, V.A. et al. Macrophages that have injested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2 and PAF. J. Clin. Invest. 101, 890–898 (1998).
McDonald, P.P., Fadok, V.A., Bratton, D. & Henson, P.M. Transcriptional and translational regulation of inflammatory mediator production by endogenous TGF-β in macrophages that have injested apoptotic cells. J. Immunol. 163, 6164–6172 (1999).
Fadok, V.A. et al. A receptor for phophatidylserine-specific clearance of apoptotic cells. Nature 405, 85–90 (2000).
Hortelano, S., Castrillo, A., Alvarez, A.M. & Boscá, L. Contribution of cyclopentenone prostaglandins to the resolution of inflammation through the potentiation of apoptosis in activated macrophages. J. Immunol. 165, 6525–6531 (2000).
Kawahito, Y. et al. 15-deoxy-Δ12,14-PGJ2 induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats. J. Clin. Invest. 106, 189–197 (2000).
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Lawrence, T., Gilroy, D., Colville-Nash, P. et al. Possible new role for NF-κB in the resolution of inflammation. Nat Med 7, 1291–1297 (2001). https://doi.org/10.1038/nm1201-1291
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DOI: https://doi.org/10.1038/nm1201-1291
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