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. 2001 Jan 15;353(Pt 2):275–281. doi: 10.1042/0264-6021:3530275

Analysis of mitogen-activated protein kinase pathways used by interleukin 1 in tissues in vivo: activation of hepatic c-Jun N-terminal kinases 1 and 2, and mitogen-activated protein kinase kinases 4 and 7.

A Finch 1, W Davis 1, W G Carter 1, J Saklatvala 1
PMCID: PMC1221569  PMID: 11139391

Abstract

The effects of interleukin 1 (IL-1) are mediated by the activation of protein kinase signalling pathways, which have been well characterized in cultured cells. We have investigated the activation of these pathways in rabbit liver and other tissues after the systemic administration of IL-1alpha. In liver there was 30-40-fold activation of c-Jun N-terminal kinase (JNK) and 5-fold activation of both JNK kinases, mitogen-activated protein kinase (MAPK) kinase (MKK)4 and MKK7. IL-1alpha also caused 2-3-fold activation of p38 MAPK and degradation of the inhibitor of nuclear factor kappaB ('IkappaB'), although no activation of extracellular signal-regulated protein kinase (ERK) (p42/44 MAPK) was observed. The use of antibodies against specific JNK isoforms showed that, in liver, short (p46) JNK1 and long (p54) JNK2 are the predominant forms activated, with smaller amounts of long JNK1 and short JNK2. No active JNK3 was detected. A similar pattern of JNK activation was seen in lung, spleen, skeletal muscle and kidney. Significant JNK3 activity was detectable only in the brain, although little activation of the JNK pathway in response to IL-1alpha was observed in this tissue. This distribution of active JNK isoforms probably results from a different expression of JNKs within the tissues, rather than from a selective activation of isoforms. We conclude that IL-1alpha might activate a more restricted set of signalling pathways in tissues in vivo than it does in cultured cells, where ERK and JNK3 activation are often observed. Cultured cells might represent a 'repair' phenotype that undergoes a broader set of responses to the cytokine.

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Selected References

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  1. Cao Z., Henzel W. J., Gao X. IRAK: a kinase associated with the interleukin-1 receptor. Science. 1996 Feb 23;271(5252):1128–1131. doi: 10.1126/science.271.5252.1128. [DOI] [PubMed] [Google Scholar]
  2. Cao Z., Xiong J., Takeuchi M., Kurama T., Goeddel D. V. TRAF6 is a signal transducer for interleukin-1. Nature. 1996 Oct 3;383(6599):443–446. doi: 10.1038/383443a0. [DOI] [PubMed] [Google Scholar]
  3. Davis W., Stephens L. R., Hawkins P. T., Saklatvala J. Synergistic activation of JNK/SAPK by interleukin-1 and platelet-derived growth factor is independent of Rac and Cdc42. Biochem J. 1999 Mar 1;338(Pt 2):387–392. [PMC free article] [PubMed] [Google Scholar]
  4. Dérijard B., Hibi M., Wu I. H., Barrett T., Su B., Deng T., Karin M., Davis R. J. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell. 1994 Mar 25;76(6):1025–1037. doi: 10.1016/0092-8674(94)90380-8. [DOI] [PubMed] [Google Scholar]
  5. Finch A., Holland P., Cooper J., Saklatvala J., Kracht M. Selective activation of JNK/SAPK by interleukin-1 in rabbit liver is mediated by MKK7. FEBS Lett. 1997 Nov 24;418(1-2):144–148. doi: 10.1016/s0014-5793(97)01364-1. [DOI] [PubMed] [Google Scholar]
  6. Freshney N. W., Rawlinson L., Guesdon F., Jones E., Cowley S., Hsuan J., Saklatvala J. Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell. 1994 Sep 23;78(6):1039–1049. doi: 10.1016/0092-8674(94)90278-x. [DOI] [PubMed] [Google Scholar]
  7. Greenfeder S. A., Nunes P., Kwee L., Labow M., Chizzonite R. A., Ju G. Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex. J Biol Chem. 1995 Jun 9;270(23):13757–13765. doi: 10.1074/jbc.270.23.13757. [DOI] [PubMed] [Google Scholar]
  8. Guesdon F., Freshney N., Waller R. J., Rawlinson L., Saklatvala J. Interleukin 1 and tumor necrosis factor stimulate two novel protein kinases that phosphorylate the heat shock protein hsp27 and beta-casein. J Biol Chem. 1993 Feb 25;268(6):4236–4243. [PubMed] [Google Scholar]
  9. Guesdon F., Knight C. G., Rawlinson L. M., Saklatvala J. Dual specificity of the interleukin 1- and tumor necrosis factor-activated beta casein kinase. J Biol Chem. 1997 Nov 28;272(48):30017–30024. doi: 10.1074/jbc.272.48.30017. [DOI] [PubMed] [Google Scholar]
  10. Gupta S., Barrett T., Whitmarsh A. J., Cavanagh J., Sluss H. K., Dérijard B., Davis R. J. Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 1996 Jun 3;15(11):2760–2770. [PMC free article] [PubMed] [Google Scholar]
  11. Ito M., Yoshioka K., Akechi M., Yamashita S., Takamatsu N., Sugiyama K., Hibi M., Nakabeppu Y., Shiba T., Yamamoto K. I. JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway. Mol Cell Biol. 1999 Nov;19(11):7539–7548. doi: 10.1128/mcb.19.11.7539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Karin M., Delhase M. JNK or IKK, AP-1 or NF-kappaB, which are the targets for MEK kinase 1 action? Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9067–9069. doi: 10.1073/pnas.95.16.9067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kracht M., Shiroo M., Marshall C. J., Hsuan J. J., Saklatvala J. Interleukin-1 activates a novel protein kinase that phosphorylates the epidermal-growth-factor receptor peptide T669. Biochem J. 1994 Sep 15;302(Pt 3):897–905. doi: 10.1042/bj3020897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kracht M., Truong O., Totty N. F., Shiroo M., Saklatvala J. Interleukin 1 alpha activates two forms of p54 alpha mitogen-activated protein kinase in rabbit liver. J Exp Med. 1994 Dec 1;180(6):2017–2025. doi: 10.1084/jem.180.6.2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kyriakis J. M., Banerjee P., Nikolakaki E., Dai T., Rubie E. A., Ahmad M. F., Avruch J., Woodgett J. R. The stress-activated protein kinase subfamily of c-Jun kinases. Nature. 1994 May 12;369(6476):156–160. doi: 10.1038/369156a0. [DOI] [PubMed] [Google Scholar]
  16. Lawler S., Cuenda A., Goedert M., Cohen P. SKK4, a novel activator of stress-activated protein kinase-1 (SAPK1/JNK). FEBS Lett. 1997 Sep 1;414(1):153–158. doi: 10.1016/s0014-5793(97)00990-3. [DOI] [PubMed] [Google Scholar]
  17. Lawler S., Fleming Y., Goedert M., Cohen P. Synergistic activation of SAPK1/JNK1 by two MAP kinase kinases in vitro. Curr Biol. 1998 Dec 17;8(25):1387–1390. doi: 10.1016/s0960-9822(98)00019-0. [DOI] [PubMed] [Google Scholar]
  18. Malinin N. L., Boldin M. P., Kovalenko A. V., Wallach D. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature. 1997 Feb 6;385(6616):540–544. doi: 10.1038/385540a0. [DOI] [PubMed] [Google Scholar]
  19. Moriguchi T., Toyoshima F., Masuyama N., Hanafusa H., Gotoh Y., Nishida E. A novel SAPK/JNK kinase, MKK7, stimulated by TNFalpha and cellular stresses. EMBO J. 1997 Dec 1;16(23):7045–7053. doi: 10.1093/emboj/16.23.7045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Muzio M., Ni J., Feng P., Dixit V. M. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science. 1997 Nov 28;278(5343):1612–1615. doi: 10.1126/science.278.5343.1612. [DOI] [PubMed] [Google Scholar]
  21. Ninomiya-Tsuji J., Kishimoto K., Hiyama A., Inoue J., Cao Z., Matsumoto K. The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature. 1999 Mar 18;398(6724):252–256. doi: 10.1038/18465. [DOI] [PubMed] [Google Scholar]
  22. Ridley S. H., Sarsfield S. J., Lee J. C., Bigg H. F., Cawston T. E., Taylor D. J., DeWitt D. L., Saklatvala J. Actions of IL-1 are selectively controlled by p38 mitogen-activated protein kinase: regulation of prostaglandin H synthase-2, metalloproteinases, and IL-6 at different levels. J Immunol. 1997 Apr 1;158(7):3165–3173. [PubMed] [Google Scholar]
  23. Rouse J., Cohen P., Trigon S., Morange M., Alonso-Llamazares A., Zamanillo D., Hunt T., Nebreda A. R. A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell. 1994 Sep 23;78(6):1027–1037. doi: 10.1016/0092-8674(94)90277-1. [DOI] [PubMed] [Google Scholar]
  24. Régnier C. H., Song H. Y., Gao X., Goeddel D. V., Cao Z., Rothe M. Identification and characterization of an IkappaB kinase. Cell. 1997 Jul 25;90(2):373–383. doi: 10.1016/s0092-8674(00)80344-x. [DOI] [PubMed] [Google Scholar]
  25. Welch H., Eguinoa A., Stephens L. R., Hawkins P. T. Protein kinase B and rac are activated in parallel within a phosphatidylinositide 3OH-kinase-controlled signaling pathway. J Biol Chem. 1998 May 1;273(18):11248–11256. doi: 10.1074/jbc.273.18.11248. [DOI] [PubMed] [Google Scholar]
  26. Whitmarsh A. J., Cavanagh J., Tournier C., Yasuda J., Davis R. J. A mammalian scaffold complex that selectively mediates MAP kinase activation. Science. 1998 Sep 11;281(5383):1671–1674. doi: 10.1126/science.281.5383.1671. [DOI] [PubMed] [Google Scholar]
  27. Whitmarsh A. J., Yang S. H., Su M. S., Sharrocks A. D., Davis R. J. Role of p38 and JNK mitogen-activated protein kinases in the activation of ternary complex factors. Mol Cell Biol. 1997 May;17(5):2360–2371. doi: 10.1128/mcb.17.5.2360. [DOI] [PMC free article] [PubMed] [Google Scholar]

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