A Novel Mechanism for TNF-α Regulation by p38 MAPK: Involvement of NF-κB with Implications for Therapy in Rheumatoid Arthritis

Journal of Immunology - Tập 173 Số 11 - Trang 6928-6937 - 2004
Jamie I. D. Campbell1, Cathleen J. Ciesielski1, Abigail E. Hunt1, Nicole J. Horwood1, Jonathan T. Beech1, Louise A. Hayes1, A Denys1, Marc Feldmann1, Fionula M. Brennan1, Brian M. J. Foxwell1
1Kennedy Institute of Rheumatology Division, Imperial College School of Medicine Hammersmith, London, United Kingdom

Tóm tắt

Abstract

TNF-α is a key factor in a variety of inflammatory diseases. This study examines the role of p38 MAPK in the regulation of TNF-α in primary human cells relevant to inflammation, e.g., macrophages and rheumatoid synovial cells. Using a dominant negative variant (D168A) of p38 MAPK and a kinase inhibitor, SB203580, we confirm in primary human macrophages that p38 MAPK regulates TNF-α production using a posttranscriptional mechanism requiring the 3′ untranslated region of the gene. However, in LPS-activated primary human macrophages we also detect a second previously unidentified mechanism, the p38 MAPK modulation of TNF-α transcription. This is mediated through p38 MAPK regulation of NF-κB. Interestingly this mechanism was not observed in rheumatoid synovial cells. Importantly however, the dominant negative mutant of p38 MAPK, but not SB203580 was effective at inhibiting spontaneous TNF-α production in these ex vivo rheumatoid synovial cell cultures. These data indicate there are potential major differences in the role of p38 MAPK in inflammatory signaling that have a bearing on the use of this kinase as a target for therapy. These results indicate despite disappointing results with p38 MAPK inhibitors in the clinic, this kinase is a valid target in rheumatoid disease.

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Tài liệu tham khảo

Feldmann, M., R. N. Maini. 2003. Lasker Clinical Medical Research Award: TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat. Med. 9:1245.

Feldmann, M., R. N. Maini. 2001. Anti-TNFα therapy of rheumatoid arthritis: what have we learned?. Annu. Rev. Immunol. 19:163.

Hammaker, D., S. Sweeney, G. S. Firestein. 2003. Signal transduction networks in rheumatoid arthritis. Ann. Rheum. Dis. 2:((62 Suppl.)):ii86.

Foxwell, B., E. Andreakos, F. Brennan, M. Feldmann, C. Smith, M. Conron. 2003. Prospects for the development of small molecular weight compounds to replace anti-tumour necrosis factor biological agents. Ann. Rheum. Dis. 2:((62 Suppl.)):ii90.

Baldwin, A. S., Jr. 1996. The NF-κB and IκB proteins: new discoveries and insights. Annu. Rev. Immunol. 14:649.

Barnes, P. J., M. Karin. 1997. Nuclear factor-κB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336:1066.

Foxwell, B., K. Browne, J. Bondeson, C. Clarke, C. de Martin, F. Brennan, M. Feldmann. 1998. Efficient adenoviral infection with IκBα reveals that macrophage tumor necrosis factor a production in rheumatoid arthritis is NF-κB dependent. Proc. Natl. Acad. Sci. USA 95:8211.

Bondeson, J., B. Foxwell, F. Brennan, M. Feldmann. 1999. Defining therapeutic targets by using adenovirus: blocking NF-κB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. Proc. Natl. Acad. Sci. USA 96:5668.

Lee, J. C., J. T. Laydon, P. C. McDonnell, T. F. Gallagher, S. Kumar, D. Green, D. McNulty, M. J. Blumenthal, J. R. Heys, S. W. Landvatter, et al 1994. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372:739.

Han, J., J. D. Lee, L. Bibbs, R. J. Ulevitch. 1994. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265:808.

Young, P., P. McDonnell, D. Dunnington, A. Hand, J. Laydon, J. Lee. 1993. Pyridinyl imidazoles inhibit IL-1 and TNF production at the protein level. Agents Actions 39:C67.

Kontoyiannis, D., M. Pasparakis, T. T. Pizarro, F. Cominelli, G. Kollias. 1999. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10:387.

Kotlyarov, A., A. Neininger, C. Schubert, R. Eckert, C. Birchmeier, H. D. Volk, M. Gaestel. 1999. MAPKAP kinase 2 is essential for LPS-induced TNF-α biosynthesis. Nat. Cell Biol. 1:94.

Wang, C. Y., D. C. Guttridge, M. W. Mayo, A. S. Baldwin, Jr. 1999. NF-κB induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis. Mol. Cell. Biol. 19:5923.

Brook, M., G. Sully, A. R. Clark, J. Saklatvala. 2000. Regulation of tumour necrosis factor α mRNA stability by the mitogen-activated protein kinase p38 signalling cascade. FEBS Lett. 483:57.

Dean, J. L., S. J. Sarsfield, E. Tsounakou, J. Saklatvala. 2003. p38 Mitogen-activated protein kinase stabilizes mRNAs that contain cyclooxygenase-2 and tumor necrosis factor AU-rich elements by inhibiting deadenylation. J. Biol. Chem. 278:39470.

Dean, J. L., M. Brook, A. R. Clark, J. Saklatvala. 1999. p38 Mitogen-activated protein kinase regulates cyclooxygenase-2 mRNA stability and transcription in lipopolysaccharide-treated human monocytes. J. Biol. Chem. 274:264.

Lali, F. V., A. E. Hunt, S. J. Turner, B. M. Foxwell. 2000. The pyridinyl imidazole inhibitor SB203580 blocks phosphoinositide-dependent protein kinase activity, protein kinase B phosphorylation, and retinoblastoma hyperphosphorylation in interleukin-2-stimulated T cells independently of p38 mitogen-activated protein kinase. J. Biol. Chem. 275:7395.

Miyazawa, K., A. Mori, H. Miyata, M. Akahane, Y. Ajisawa, H. Okudaira. 1998. Regulation of interleukin-1β-induced interleukin-6 gene expression in human fibroblast-like synoviocytes by p38 mitogen-activated protein kinase. J. Biol. Chem. 273:24832.

Xu, N., C. Y. Chen, A. B. Shyu. 1997. Modulation of the fate of cytoplasmic mRNA by AU-rich elements: key sequence features controlling mRNA deadenylation and decay. Mol. Cell. Biol. 17:4611.

Lasa, M., K. R. Mahtani, A. Finch, G. Brewer, J. Saklatvala, A. R. Clark. 2000. Regulation of cyclooxygenase 2 mRNA stability by the mitogen-activated protein kinase p38 signaling cascade. Mol. Cell. Biol. 20:4265.

Winzen, R., M. Kracht, B. Ritter, A. Wilhelm, C. Y. Chen, A. B. Shyu, M. Muller, M. Gaestel, K. Resch, H. Holtmann. 1999. The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism. EMBO J. 18:4969.

Chen, K. D., L. Y. Chen, H. L. Huang, C. H. Lieu, Y. N. Chang, M. D. Chang, Y. K. Lai. 1998. Involvement of p38 mitogen-activated protein kinase signaling pathway in the rapid induction of the 78-kDa glucose-regulated protein in 9L rat brain tumor cells. J. Biol. Chem. 273:749.

Han, J., Y. Jiang, Z. Li, V. V. Kravchenko, R. J. Ulevitch. 1997. Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation. Nature 386:296.

Wang, X. Z., D. Ron. 1996. Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP kinase. Science 272:1347.

Raingeaud, J., A. J. Whitmarsh, T. Barrett, B. Derijard, R. J. Davis. 1996. MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol. Cell. Biol. 16:1247.

Vermeulen, L., G. De Wilde, P. Van Damme, W. Vanden Berghe, G. Haegeman. 2003. Transcriptional activation of the NF-κB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J. 22:1313.

Saccani, S., S. Pantano, G. Natoli. 2002. p38-Dependent marking of inflammatory genes for increased NF-κB recruitment. Nat. Immunol. 3:69.

Bowie, A. G., L. A. O’Neill. 2000. Vitamin C inhibits NF-κB activation by TNF via the activation of p38 mitogen-activated protein kinase. J. Immunol. 165:7180.

Alpert, D., P. Schwenger, J. Han, J. Vilcek. 1999. Cell stress and MKK6b-mediated p38 MAP kinase activation inhibit tumor necrosis factor-induced IκB phosphorylation and NF-κB activation. J. Biol. Chem. 274:22176.

Buchan, G., K. Barrett, M. Turner, D. Chantry, R. N. Maini, M. Feldmann. 1988. Interleukin-1 and tumour necrosis factor mRNA expression in rheumatoid arthritis: prolonged production of IL-1α. Clin. Exp. Immunol. 73:449.

He, T. C., S. Zhou, L. T. da Costa, J. Yu, K. W. Kinzler, B. Vogelstein. 1998. A simplified system for generating recombinant adenoviruses. Proc. Natl. Acad. Sci. USA 95:2509.

Udalova, I. A., A. Richardson, A. Denys, C. Smith, H. Ackerman, B. Foxwell, D. Kwiatkowski. 2000. Functional consequences of a polymorphism affecting NF-κB p50–p50 binding to the TNF promoter region. Mol. Cell. Biol. 20:9113.

Sanlioglu, S., C. M. Williams, L. Samavati, N. S. Butler, G. Wang, P. B. McCray, Jr, T. C. Ritchie, G. W. Hunninghake, E. Zandi, J. F. Engelhardt. 2001. Lipopolysaccharide induces Rac1-dependent reactive oxygen species formation and coordinates tumor necrosis factor-α secretion through IKK regulation of NF-κB. J. Biol. Chem. 276:30188.

Bondeson, J., F. Brennan, B. Foxwell, M. Feldmann. 2000. Effective adenoviral transfer of IκBα into human fibroblasts and chondrosarcoma cells reveals that the induction of matrix metalloproteinases and proinflammatory cytokines is nuclear factor-κB dependent. J. Rheumatol. 27:2078.

Hunt, A. E., F. V. Lali, J. D. Lord, B. H. Nelson, T. Miyazaki, K. J. Tracey, B. M. Foxwell. 1999. Role of interleukin (IL)-2 receptor β-chain subdomains and Shc in p38 mitogen-activated protein (MAP) kinase and p54 MAP kinase (stress-activated protein kinase/c-Jun N-terminal kinase) activation: IL-2-driven proliferation is independent of p38 and p54 MAP kinase activation. J. Biol. Chem. 274:7591.

Baldassare, J. J., Y. Bi, C. J. Bellone. 1999. The role of p38 mitogen-activated protein kinase in IL-1β transcription. J. Immunol. 162:5367.

Denys, A., I. A. Udalova, C. Smith, L. M. Williams, C. J. Ciesielski, J. Campbell, C. Andrews, D. Kwaitkowski, B. M. Foxwell. 2002. Evidence for a dual mechanism for IL-10 suppression of TNF-α production that does not involve inhibition of p38 mitogen-activated protein kinase or NF-κB in primary human macrophages. J. Immunol. 168:4837.

Horwood, N. J., T. Mahon, J. P. McDaid, J. Campbell, H. Mano, F. M. Brennan, D. Webster, B. M. Foxwell. 2003. Bruton’s tyrosine kinase is required for lipopolysaccharide-induced tumor necrosis factor α production. J. Exp. Med. 197:1603.

Kumar, S., J. Boehm, J. C. Lee. 2003. p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat. Rev. Drug. Discov. 2:717.

Nick, J. A., N. J. Avdi, S. K. Young, L. A. Lehman, P. P. McDonald, S. C. Frasch, M. A. Billstrom, P. M. Henson, G. L. Johnson, G. S. Worthen. 1999. Selective activation and functional significance of p38α mitogen-activated protein kinase in lipopolysaccharide-stimulated neutrophils. J. Clin. Invest. 103:851.

Kuprash, D. V., I. A. Udalova, R. L. Turetskaya, D. Kwiatkowski, N. R. Rice, S. A. Nedospasov. 1999. Similarities and differences between human and murine TNF promoters in their response to lipopolysaccharide. J. Immunol. 162:4045.

Carter, A. B., K. L. Knudtson, M. M. Monick, G. W. Hunninghake. 1999. The p38 mitogen-activated protein kinase is required for NF-κB-dependent gene expression: the role of TATA-binding protein (TBP). J. Biol. Chem. 274:30858.

Andreakos, E., C. Smith, S. Kiriakidis, C. Monaco, R. de Martin, F. M. Brennan, E. Paleolog, M. Feldmann, B. M. Foxwell. 2003. Heterogeneous requirement of IκB kinase 2 for inflammatory cytokine and matrix metalloproteinase production in rheumatoid arthritis: implications for therapy. Arthritis. Rheum. 48:1901.

Brennan, F. M.. 2001. A follow-up to “Anti-cytokine therapy in chronic destructive arthritis” by Wim B van den Berg. Arthritis Res. 3:211.