Abstract
Activation of T cells results in the production of lymphokines and cellular proliferation. Protein kinase C (PKC) plays a key role in this process. It has been shown that this enzyme is essential to elicit a response to Con A or specific antigen in CD4+ T helper type 1 (Th 1) cells that secrete IL-2. We have now explored the signal transduction pathway that leads to transcription of the IL-4 gene and proliferation in murine CD4+ T helper type 2 (Th 2) cells. Surprisingly, we have found in two independently derived Th 2 clones that neither cellular proliferation nor IL-4 lymphokine production is affected by blocking or depletion of PKC. This differential mechanism of signal transmission leading to cellular activation implies a new distinction between murine Th 1 and Th 2 cells.
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- Auffray C., Rougeon F. Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur J Biochem. 1980 Jun;107(2):303–314. doi: 10.1111/j.1432-1033.1980.tb06030.x. [DOI] [PubMed] [Google Scholar]
- Bell R. M. Protein kinase C activation by diacylglycerol second messengers. Cell. 1986 Jun 6;45(5):631–632. doi: 10.1016/0092-8674(86)90774-9. [DOI] [PubMed] [Google Scholar]
- Bennett C. F., Crooke S. T. Purification and characterization of a phosphoinositide-specific phospholipase C from guinea pig uterus. Phosphorylation by protein kinase C in vivo. J Biol Chem. 1987 Oct 5;262(28):13789–13797. [PubMed] [Google Scholar]
- Berridge M. J. Inositol trisphosphate and diacylglycerol: two interacting second messengers. Annu Rev Biochem. 1987;56:159–193. doi: 10.1146/annurev.bi.56.070187.001111. [DOI] [PubMed] [Google Scholar]
- Besterman J. M., Duronio V., Cuatrecasas P. Rapid formation of diacylglycerol from phosphatidylcholine: a pathway for generation of a second messenger. Proc Natl Acad Sci U S A. 1986 Sep;83(18):6785–6789. doi: 10.1073/pnas.83.18.6785. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bocckino S. B., Blackmore P. F., Wilson P. B., Exton J. H. Phosphatidate accumulation in hormone-treated hepatocytes via a phospholipase D mechanism. J Biol Chem. 1987 Nov 5;262(31):15309–15315. [PubMed] [Google Scholar]
- Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
- Cantrell D. A., Smith K. A. The interleukin-2 T-cell system: a new cell growth model. Science. 1984 Jun 22;224(4655):1312–1316. doi: 10.1126/science.6427923. [DOI] [PubMed] [Google Scholar]
- Carafoli E. Intracellular calcium homeostasis. Annu Rev Biochem. 1987;56:395–433. doi: 10.1146/annurev.bi.56.070187.002143. [DOI] [PubMed] [Google Scholar]
- Cherwinski H. M., Schumacher J. H., Brown K. D., Mosmann T. R. Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med. 1987 Nov 1;166(5):1229–1244. doi: 10.1084/jem.166.5.1229. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chilson O. P., Kelly-Chilson A. E. Mitogenic lectins bind to the antigen receptor on human lymphocytes. Eur J Immunol. 1989 Feb;19(2):389–396. doi: 10.1002/eji.1830190225. [DOI] [PubMed] [Google Scholar]
- Church G. M., Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. doi: 10.1073/pnas.81.7.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Daniel L. W., Waite M., Wykle R. L. A novel mechanism of diglyceride formation. 12-O-tetradecanoylphorbol-13-acetate stimulates the cyclic breakdown and resynthesis of phosphatidylcholine. J Biol Chem. 1986 Jul 15;261(20):9128–9132. [PubMed] [Google Scholar]
- Dinarello C. A., Clark B. D., Puren A. J., Savage N., Rosoff P. M. The interleukin 1 receptor. Immunol Today. 1989 Feb;10(2):49–51. doi: 10.1016/0167-5699(89)90304-6. [DOI] [PubMed] [Google Scholar]
- Evans S. W., Farrar W. L. Interleukin 2 and diacylglycerol stimulate phosphorylation of 40 S ribosomal S6 protein. Correlation with increased protein synthesis and S6 kinase activation. J Biol Chem. 1987 Apr 5;262(10):4624–4630. [PubMed] [Google Scholar]
- Farrar W. L., Anderson W. B. Interleukin-2 stimulates association of protein kinase C with plasma membrane. Nature. 1985 May 16;315(6016):233–235. doi: 10.1038/315233a0. [DOI] [PubMed] [Google Scholar]
- Friedrich B., Cantrell D. A., Gullberg M. Increased cyclic AMP levels block interleukin 2-induced protein kinase C substrate phosphorylation but not the mitogenic response. Eur J Immunol. 1989 Jun;19(6):1111–1116. doi: 10.1002/eji.1830190622. [DOI] [PubMed] [Google Scholar]
- Greenbaum L. A., Horowitz J. B., Woods A., Pasqualini T., Reich E. P., Bottomly K. Autocrine growth of CD4+ T cells. Differential effects of IL-1 on helper and inflammatory T cells. J Immunol. 1988 Mar 1;140(5):1555–1560. [PubMed] [Google Scholar]
- Hidaka H., Inagaki M., Kawamoto S., Sasaki Y. Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochemistry. 1984 Oct 9;23(21):5036–5041. doi: 10.1021/bi00316a032. [DOI] [PubMed] [Google Scholar]
- Isakov N., Mally M. I., Scholz W., Altman A. T-lymphocyte activation: the role of protein kinase C and the bifurcating inositol phospholipid signal transduction pathway. Immunol Rev. 1987 Feb;95:89–111. doi: 10.1111/j.1600-065x.1987.tb00501.x. [DOI] [PubMed] [Google Scholar]
- Kaye J., Porcelli S., Tite J., Jones B., Janeway C. A., Jr Both a monoclonal antibody and antisera specific for determinants unique to individual cloned helper T cell lines can substitute for antigen and antigen-presenting cells in the activation of T cells. J Exp Med. 1983 Sep 1;158(3):836–856. doi: 10.1084/jem.158.3.836. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kikkawa U., Nishizuka Y. The role of protein kinase C in transmembrane signalling. Annu Rev Cell Biol. 1986;2:149–178. doi: 10.1146/annurev.cb.02.110186.001053. [DOI] [PubMed] [Google Scholar]
- Kuno M., Gardner P. Ion channels activated by inositol 1,4,5-trisphosphate in plasma membrane of human T-lymphocytes. Nature. 1987 Mar 19;326(6110):301–304. doi: 10.1038/326301a0. [DOI] [PubMed] [Google Scholar]
- Kupper T., Horowitz M., Lee F., Robb R., Flood P. M. Autocrine growth of T cells independent of interleukin 2: identification of interleukin 4 (IL 4, BSF-1) as an autocrine growth factor for a cloned antigen-specific helper T cell. J Immunol. 1987 Jun 15;138(12):4280–4287. [PubMed] [Google Scholar]
- Kurt-Jones E. A., Hamberg S., Ohara J., Paul W. E., Abbas A. K. Heterogeneity of helper/inducer T lymphocytes. I. Lymphokine production and lymphokine responsiveness. J Exp Med. 1987 Dec 1;166(6):1774–1787. doi: 10.1084/jem.166.6.1774. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lichtman A. H., Chin J., Schmidt J. A., Abbas A. K. Role of interleukin 1 in the activation of T lymphocytes. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9699–9703. doi: 10.1073/pnas.85.24.9699. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lichtman A. H., Kurt-Jones E. A., Abbas A. K. B-cell stimulatory factor 1 and not interleukin 2 is the autocrine growth factor for some helper T lymphocytes. Proc Natl Acad Sci U S A. 1987 Feb;84(3):824–827. doi: 10.1073/pnas.84.3.824. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mills G. B., Cheung R. K., Grinstein S., Gelfand E. W. Increase in cytosolic free calcium concentration is an intracellular messenger for the production of interleukin 2 but not for expression of the interleukin 2 receptor. J Immunol. 1985 Mar;134(3):1640–1643. [PubMed] [Google Scholar]
- Mills G. B., Girard P., Grinstein S., Gelfand E. W. Interleukin-2 induces proliferation of T lymphocyte mutants lacking protein kinase C. Cell. 1988 Oct 7;55(1):91–100. doi: 10.1016/0092-8674(88)90012-8. [DOI] [PubMed] [Google Scholar]
- Mizuguchi J., Ji Y. Y., Nakabayaschi H., Huang K. P., Beaven M. A., Chused T., Paul W. E. Protein kinase C activation blocks anti-IgM-mediated signaling BAL17 B lymphoma cells. J Immunol. 1987 Aug 15;139(4):1054–1059. [PubMed] [Google Scholar]
- Murayama T., Ui M. Phosphatidic acid may stimulate membrane receptors mediating adenylate cyclase inhibition and phospholipid breakdown in 3T3 fibroblasts. J Biol Chem. 1987 Apr 25;262(12):5522–5529. [PubMed] [Google Scholar]
- Muñoz E., Beutner U., Zubiaga A., Huber B. T. IL-1 activates two separate signal transduction pathways in T helper type II cells. J Immunol. 1990 Feb 1;144(3):964–969. [PubMed] [Google Scholar]
- Muñoz E., Zubiaga A., Olson D., Huber B. T. Control of lymphokine expression in T helper 2 cells. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9461–9464. doi: 10.1073/pnas.86.23.9461. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nishimura T., Burakoff S. J., Herrmann S. H. Protein kinase C required for cytotoxic T lymphocyte triggering. J Immunol. 1987 Nov 1;139(9):2888–2891. [PubMed] [Google Scholar]
- Nishizuka Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature. 1988 Aug 25;334(6184):661–665. doi: 10.1038/334661a0. [DOI] [PubMed] [Google Scholar]
- Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature. 1984 Apr 19;308(5961):693–698. doi: 10.1038/308693a0. [DOI] [PubMed] [Google Scholar]
- Rozengurt E., Rodriguez-Pena M., Smith K. A. Phorbol esters, phospholipase C, and growth factors rapidly stimulate the phosphorylation of a Mr 80,000 protein in intact quiescent 3T3 cells. Proc Natl Acad Sci U S A. 1983 Dec;80(23):7244–7248. doi: 10.1073/pnas.80.23.7244. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sando J. J., Hilfiker M. L., Salomon D. S., Farrar J. J. Specific receptors for phorbol esters in lymphoid cell populations: role in enhanced production of T-cell growth factor. Proc Natl Acad Sci U S A. 1981 Feb;78(2):1189–1193. doi: 10.1073/pnas.78.2.1189. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shaw G., Kamen R. A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell. 1986 Aug 29;46(5):659–667. doi: 10.1016/0092-8674(86)90341-7. [DOI] [PubMed] [Google Scholar]
- Tony H. P., Phillips N. E., Parker D. C. Role of membrane immunoglobulin (Ig) crosslinking in membrane Ig-mediated, major histocompatibility-restricted T cell-B cell cooperation. J Exp Med. 1985 Nov 1;162(5):1695–1708. doi: 10.1084/jem.162.5.1695. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Truneh A., Albert F., Golstein P., Schmitt-Verhulst A. M. Early steps of lymphocyte activation bypassed by synergy between calcium ionophores and phorbol ester. Nature. 1985 Jan 24;313(6000):318–320. doi: 10.1038/313318a0. [DOI] [PubMed] [Google Scholar]
- Valge V. E., Wong J. G., Datlof B. M., Sinskey A. J., Rao A. Protein kinase C is required for responses to T cell receptor ligands but not to interleukin-2 in T cells. Cell. 1988 Oct 7;55(1):101–112. doi: 10.1016/0092-8674(88)90013-x. [DOI] [PubMed] [Google Scholar]
- Weiss A., Wiskocil R. L., Stobo J. D. The role of T3 surface molecules in the activation of human T cells: a two-stimulus requirement for IL 2 production reflects events occurring at a pre-translational level. J Immunol. 1984 Jul;133(1):123–128. [PubMed] [Google Scholar]
- Wilson D. B., Bross T. E., Hofmann S. L., Majerus P. W. Hydrolysis of polyphosphoinositides by purified sheep seminal vesicle phospholipase C enzymes. J Biol Chem. 1984 Oct 10;259(19):11718–11724. [PubMed] [Google Scholar]
- Yamamoto Y., Ohmura T., Kawakami K., Onoue K., Hidaka H. Induction and regulation of human interleukin 2 gene expression: significance of protein kinase C activation. J Biochem. 1986 Aug;100(2):333–340. doi: 10.1093/oxfordjournals.jbchem.a121719. [DOI] [PubMed] [Google Scholar]