Summary
Circulating filarial proteins elicit strong immunologic reactions in humans leading to the chronic manifestations in human lymphatic filariasis such as lymphatic occlusion, fibrosis, edema, and in some cases, tropical pulmonary eosinophilia. Our earlier studies, in vitro, conclusively prove that filarial parasitic sheath proteins induce apoptosis in HEp2 cells, an epithelial cell line, by a pathwa inhibitable by bcl2. The present findings provide evidence that c-myc activation triggers apoptosis in HEp2 cells and that it is also responsible for the burst of abortive proliferation at 6 d of treatment of HEp2 bcl2 cells that overexpress bcl2, with filarial parasitic sheath protein, demonstrating the interplay between the two genes c-myc and bcl2, wherein bcl2 acts by restoring the prosurvival signal to c-myc and keeping its apoptotic tendency in check. This study also indicates that bcl2 upregulates c-H-ras, engaring ras to bring about the suppression of apoptosis through protein tyrosine kinase elevation, thus promoting the survival of the HEp2 bcl2 cells. In addition to the activation of these “signal switches,” we also observe that these cells release cytokines like IL-6 and IL-8 through the upregulation of c-fos, when exposed to filarial parasitic sheath protein, reflecting on the immunomodulatory capacity of the epithelium to elicit a host immune response by setting up a chemotactic gradient, attracting inflammatory cells to the site of infection.
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References
Afar, D. E. H.; Goga, A.; McLaughlin, J.; Witte, O. N.; Sawyers, C. L. Differential complementation of BCR-ABL point mutants with c-myc. Science 264:424–426; 1994.
Agace, W.; Hedges, S.; Andersson, U.; Andersson, J.; Ceska, M.; Svanborg, C. Selective cytokine production by epithelial cells following exposure to Escherichia coli. Infect. Immun. 61:602–609; 1993.
Baggiolini, M.; Walz, A.; Kunkel, S. L. Neutrophil activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J. Clin. Invetig. 84:1045–1049; 1989.
Beuria, M. K.; Das, M. K. Immune responses to an allergenic fraction of Setaria digitata in human filariasis. J. Biosci. 17:453–461; 1992.
Bissonnette, R. P.; Echeverri, F.; Mahboubi, A.; Green, D. R. Apoptotic cell death induced by c-myc is inhibited by bcl2. Nature 359(6395):552–554; 1992.
Campbell, S. L.; Khosravi-Far, R.; Rossman, K. L.; Clark, G. J.; Der, C. J. Increasing complexity of ras signaling. Oncogene 17:1395–1413; 1998.
Chen, C. Y.; Liou, J.; Forman, L. W.; Faller, D. V. Differential regulation of apoptotic pathways by ras. J. Biol. Chem. 273:16700–16709; 1998.
Cortez, D.; Stoica, G.; Pierce, J. H.; Pendergast A. M. The BCR-ABL tyrosine kinase inhibits apoptosis b activating a ras-dependent signalling pathway. Oncogene 13:2589–2594; 1996.
Cromwell, O.; Hamid, Q.; Corrigan, C. J.; Barkans, J.; Meng, Q.; Collins, P. D. Expression and generation of interleukin 6, interleukin 8 and granulocyte-macrophage colony stimulating factor by bronchial epithelial cells and enhancement by interleukin 1β and tumor necrosis factor α. Immunology 77:330–337; 1992.
Daum, G.; Eisenmann-Tappe, I.; Fries, H. W.; Troppmair, J.; Rapp, U. R. Ins and outs of Raf kinases. Trends Biochem. Sci. 19:474–480; 1994.
Downward, J. ras signalling and apoptosis. Curr. Opinion Genet. Dev. 8:49–54; 1998.
Eilers, M.; Picard, D.; Yamamota, K. R.; Bishop, M. J. Chimaeras of myc oncoproteins and steroid receptors cause hormone-dependent transformation of cells. Nature 340:66–68; 1989.
Eilers, M.; Schiem, S.; Bishop, J. M. The myc protein activates transcription of the alpha-prothymosin gene. EMBO J. 10:133–141; 1991.
Evan, G. I. Induction of apoptosis in fibroblasts by c-myc protein. Cell 69: 119–128; 1992.
Evan, G. I.; Littlewood, T. D. The role of c-myc in cell growth. Curr. Opinion Genet. Dev. 3:44–49; 1993.
Graham, F. L.; van der Eb, A. J. A new technique for the assay of infectivity of adenovirus 5 DNA. Virology 52:456; 1973.
Grigg, J. M.; Barber, A. Increased levels of bronchoalveolar lavage fluid interleukin 6 secretion by alveolar macrophages in preterm ventilated infants after prolonged rupture of membranes. Am. Rev. Respir. Dis. 145:782–786; 1992.
Jarpe, M. B.; Widmann, C.; Knall, C., et al. Anti-apoptotic versus pro-apoptotic signal transduction: checkpoints and stop signs along the road to death. Oncogene 17:1475–1482; 1998.
Jones, K. P.; Reynolds, S. P.; Capper, S. J.; Kalinka, S.; Edwards, J. H.; Davies, B. H. Measurement of interleukin 6 in bronchoalveolar lavage fluid by radioimmunoassay: differences in patients with interstitial lung disease and control subjects. Clin. Exp. Immunol. 83:30–34; 1991.
Kelley, J. Cytokines of the lung. Am. Rev. Respir. Dis. 141:765–788; 1990.
Keul, R.; Roth, M.; Papakonstantinou, E.; Nauck, M.; Perruchoud, A. P.; Block, L. H. Induction of interleukin-8 expression by Broncho-Vascom (OM-85 BV) via c-fos/serum responsive element. Thorax 51:150–154, 1996.
King, K. L.; Cidlowski, J. A. Cell cycle and apoptosis: common pathways to life and death. J. Cell. Biochem. 58:175–180; 1995.
Kinoshita, T.; Yokota, T.; Arai, K.; Miyajima, A. Regulation of bcl2 expression by oncogenic ras protein in haematopoietic cells. Oncogene 10:2207–2212; 1995.
Krishnamoorthy, B.; Renner, W.; Balakrishnan, A. Filarial parasitic sheath proteins—induced apoptosis in HEp2 cell lines blocked by the ectopic expression of bcl2. Cell Biol. Int. 22:483–493; 1998.
Lee, S.; Christakos, S.; Small, M. B. Apoptosis and signal transduction: clues to a molecular mechanism. Curr. Opinion Cell Biol. 5:286–291; 1993.
Marks, F.; Boukamp, P. Signal transduction and mechanisms of cell death. Sixth colloquium on cellular signal transduction. J. Cancer Res. Clin. Oncol. 123:522–526; 1997.
May Jr., W. S. Control of apoptosis by cytokines. Adv. Pharmacol. 41:219–246; 1997.
Maya, A.; Usha, S.; Jayaraman, K.; Baba, K.; Sukumaran, M.; Balakrishnan, A. Interaction of filarial proteins on growth regulation of normal lung epithelial cells in vitro. Cell Biol. Int. 19:223–231; 1995.
Nutman, T. B.; Vijayan, V. K.; Pinkston, P.; Kumaraswami, V.; Stell, C.; Crystal, R. G.; Ottesen, E. A. Tropical pulmonary eosinophilia: analysis of antifilarial antibody localised to the lung. J. Infect. Dis. 160:1042–1050; 1989.
Ottesen, E. A. Immunological aspects of lymphatic filariasis and onchocerciasis in man. Trans. Soc. Trop. Med. Hygi. 78 (Suppl):9–18, 1984.
Packham, G.; Cleveland, J. L. c-myc and apoptosis. Biochim. Biophys. Acta 1242:11–28; 1995.
Reed, J. C. bcl2 and the regulation of programmed cell death. J. Cell Biol. 124:1–6; 1994.
Roth, M.; Nauck, M.; Yousefi, S.; Tamm, M.; Blaser, K.; Perruchoud, A. P.; Simon, H. U. Platelet activating factor exerts mitogenic activity and stimulates expression of interleukin 6 and interleukin 8 in human lung fibroblasts via binding to its functional receptor. J. Exp. Med. 184:191–201; 1996.
Sakamuro, D.; Eviner, V.; Elliot, K. J.; Showe, L.; White, E.; Prendergast, C. c-myc induces apoptosis in epithelial cells by both p53-dependent and p53-independent mechanism. Oncogene 11:2411–2418; 1995.
Sanchez-Garcia, I.; Martin-Zanca, D. Regulation of bcl2 gene expression by BCR-ABL is mediated by ras. J. Mol. Biol. 267:225–228; 1997.
Sawyers, C. L.; Callaham, W.; Witte, O. N. Dominant negative MYC blocks transformation by ABL oncogenes. Cell 70:901–910; 1992.
Southern, P. J.; Berg, P. Transformation of mammalian cells to antibiotic resistance with a bacterial gene under control of SV40 early region promoter. J. Mol. Appl. Genet. 1:327–341; 1982.
Stadnyk, A. W. Cytokine production by epithelial cells. FASEB J. 8:1041–1047; 1994.
Standiford, T. J.; Kunkel, S. L.; Basha, M. A.; Chensue, S. W.; Lynch III, J. P.; Toews, G. B.; Westwick, J.; Strieter, R. M. Interleukin-8 gene expression by a pulmonary epithelial cell line—a model for cytokine networks in the lung. J. Clin. Invest. 86:1945–1953; 1990.
Stewart, B. W. Mechanisms of apoptosis: integration of genetic, biochemical and cellular mediators. J. Natl. Cancer Inst. 86:1286–1296; 1994.
Theodore, G. J.; Kaliraj, P. Isolation, purification and characterisation of surface antigens of the bovine filarial parasite Setaria digitata for the immunodiagnosis of bancroftian filariasis. J. Helminthol. 64:105–114; 1990.
Vaux, D. L. Towards an understanding of the molecular mechanisms of physiological cell death. Proc. Natl. Acad. Sci. USA 90:786–789; 1993.
Wang, H. G.; Rapp, U. R.; Reed, J. C. bcl2 targets the protein kinase Raf-1 to mitochondria. Cell 87:629–638; 1996.
Wu, W. Analysis of gene expression at the RNA level. In: Methods in gene biotechnology. Boca Raton, FL: CRC Press; 1993:225–239.
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Krishnamoorthy, B., Narayanan, K., Miyamoto, S. et al. Epithelial cells release proinflammatory cytokines and undergo c-myc-induced apoptosis on exposure to filarial parasitic sheath protein-Bcl2 mediates rescue by activating c-H-ras . In Vitro Cell.Dev.Biol.-Animal 36, 532–538 (2000). https://doi.org/10.1290/1071-2690(2000)036<0532:ECRPCA>2.0.CO;2
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DOI: https://doi.org/10.1290/1071-2690(2000)036<0532:ECRPCA>2.0.CO;2