|Programmed cell death or apoptosis is one of the major contributors to the development of a normal immune system, the developmentally correct architecture of tissues and organs and the proper maintenance of organ homeostasis. However, dysfunctional induction of apoptosis appears to be critical for the aberrant survival of pathological cells in many chronic immune-mediated disorders, inflammation and cancer.
|This Special Issue of the Journal of Clinical and Cellular Immunology devoted to “Immune Response and Apoptosis” reviews the recent advances in our understanding of how the balance between cell survival and apoptosis is regulated and maintained in the normal state including the role apoptosis plays in regulating T-lymphocyte development, how apoptosis acts as a fundamental cellular process responsible for suppressing the activity of antigen-presenting dendritic cells (DCs) a key step in controlling immune tolerance, and how apoptosis acts as the critical modulator of innate and adaptive immunity.
|Several pathologies are also reviewed. These disorders are characterized either by an abnormally low frequency of apoptosis with a skewed number of pathological cells surviving and outnumbering those deleted by apoptosis or by the aberrant deletion and lost vitality of normal cells. Thus, aberrant apoptosis is intimately associated with both the pathogenesis and progression of chronic inflammatory diseases such as intestinal bowel disease (IBD), rheumatoid arthritis (RA) and necrotizing enterocolitis (NEC). Finally, from a therapeutic perspective, ganoderic acids are proposed as drugs which modulate cancer cell proliferation and immune cell activation via their capacity to induce apoptosis. This focus demonstrates the chemotherapeutic potential of natural products in influencing research in this area.
|Apoptosis Regulates Normal Immune Cell Development
|Carolina Francelin and Liana Verinaud (Institute of Biology, State University of Campinas, São Paulo, BRAZIL) review the evidence that apoptosis regulates T-lymphocyte (i.e. T-cells) development through positive and negative selection [1-3]. Of note, the results of several studies [4-6] have shown that T-cell receptor (TCR)-independent, ligand-induced TCR-signaling and the relative expression of pro- and anti-apoptotic proteins during intrathymic development lead either to rescue from cell death through positive T-cell selection and/or cell death via negative T-cell selection.
|DCs are considered the most efficient antigen-presenting cells in both lymphoid and non-lymphoid tissues . Min Chen and Jin Wang (Baylor College of Medicine, Houston, Texas, USA) review the accumulated evidence showing that dysregulated DC apoptosis results in abnormal DC survival which is associated with the development of systemic autoimmune diseases [8,9]. Thus, maintenance of the correct number and activity of DCs is required for maintaining immune system homeostasis, including the capacity to orchestrate appropriate inflammatory responses and the regulation of immune tolerance.
|A detailed review of apoptosis as the ultimate immunomodulatory cellular event is presented by Anuradha K. Murali and Shikhar Mehrotra (Medical University of South Carolina, Charleston, South Carolina, USA). These investigators point out that impairment of apoptotic pathways or the lack of strict regulation of apoptosis results in autoimmune and inflammatory disorders, viral and bacterial infections as well as cancer. Importantly, recent evidence implicating specific microRNAs in regulating a special form of T-cell death called rapid-activation-induced cell death  is discussed.
|Role of Impaired Apoptosis in IBD, RA and NEC
|IBD is a term used to describe two mutually independent yet chronic inflammatory conditions of the intestine namely, ulcerative colitis and Crohn’s disease. Importantly, key mediators of apoptosis and autophagy are implicated in the genetic susceptibility, pathogenesis and perpetuation of IBD [11-13]. Michael Schnoor (Max-Planck-Institute of Molecular Biomedicine, Münster, GERMANY) and Nancy A. Louis (Emory University School of Medicine, Atlanta, Georgia, USA) review how pro-inflammatory cytokines skew the balance between pro- and anti-apoptotic responses of the intestinal epithelium that primarily result from activation of key pathways involving type I  and type II interferon proteins , nuclear factor-κB (NF-κB) , and Wntmediated signaling [17,18], as well as the role that oxygen tension  and nutritional factors  play in regulating these pathways.
|In RA, elevated levels of the pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-(IL)-1β, IL-6, IL-17 and interferon-γ, among others, results in a skewing of the balance between the survival of cells in synovial tissue and apoptosis, favoring the former. Charles J. Malemud (Case Western Reserve University School of Medicine, Cleveland, Ohio, USA) reviews the cellular mechanisms in RA that favor synoviocyte, immune and inflammatory cell activation, proliferation and survival with resultant synovial tissue hyperplasia and chronic inflammation characterized by resistance to apoptosis. This resistance to apoptosis has been connected to a deregulated activation of the Stress-Activated Protein Kinase/Mitogen-Activated Protein Kinase (SAPK/MAPK) and the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathways by these cytokines and also by “cross-talk” between activated SAPK/MAPK and JAK/STAT pathways and the PI3/Akt/PTEN/mTOR pathway, the latter favoring the survival of activated synoviocytes, immune and inflammatory cells in RA synovium [21-26]. Furthermore, the mechanism(s) of action whereby disease-modifying anti-rheumatic drugs (e.g. methotrexate) and/or disease modifying anti-rheumatic biologic drugs (e.g. TNF-α antagonists, IL-1 receptor antagonist, IL-6 receptor antagonist) suppress the clinical activity of RA is also discussed focusing on how these therapeutic interventions may also play a crucial role in restoring the balance between cell survival and apoptosis in RA synovial tissue [27-29].
|Tamas Jilling, Jing Lu and Michael Caplan (NorthShore University Health System Research Institute and University of Chicago Pritzker School of Medicine, Evanston, Illinois, USA) review the evidence demonstrating the role that deregulated enterocyte apoptosis plays in the pathogenesis of NEC. They point out the potentially critical role played by several inflammatory mediators including platelet-activating factor, TNF-α, Toll-like receptors and IL-8 [30-33] in activating signal transduction pathways that cause mucosal injury as reflected by the activation of mitochondrial-derived pro-caspase(s) and NF-κB activation.
|Chemotherapy with Ganoderic Acid Induces Apoptosis
|The anti-tumor properties of the Ganoderma lucidum mushroom are reviewed by Faisal F.Y. Radwan, J. Manuel Perez and Azizul Haque (Medical University of South Carolina, Charleston, South Carolina, USA). The ganoderic acids are methanol-soluble triterpenoids  derived from Ganoderma lucidum with potent cancer chemotherapeutic activity . Although significant compelling evidence reveals that ganoderic acids induce apoptosis in cancer cells [36-38] with a lower toxicity towards normal cells, more recently published data showed that ganoderic acids can also alter the immune system and its antitumor activity [39,40]. The long-term goal of employing nanoparticle polymer-coated  ganoderic acid for the targeted delivery of these Ganoderma lucidum-derived compounds to malignant tissues in vivo is also discussed.
|Taken together, these reviews underscore the critical nature of the tight regulation of apoptosis in development, inflammation, and cancer. It is clear that apoptotic pathways provide promising targets for the prevention or attenuation of disease in multiple tissues. However, the complex balance of pro- and anti-apoptotic proteins regulating cellular function and tissue homeostasis must be considered during the rationale design of cell and tissue-specific tools to manipulate these processes.
|The authors disclose no conflict of interest.
- Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC, et al. (2003) Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 426: 671-676.
- Hu MG, Deshpande A, Schlichting N, Hinds EA, Mao C, et al. (2011) CDK6 kinase activity is required for thymocyte development. Blood 117: 6120-6131.
- Juntilla MM, Wofford JA, Birnbaum MJ, Rathmell JC, Koretsky GA (2007) Akt1 and Akt2 are required for αβ thymocyte survival and differentiation. Proc Natl Acad Sci USA 104: 12105-12110.
- Wolfer A, Wilson A, Nemir M, MacDonald HR, Radtke F (2002) Inactivation of Notch1 impairs VDJβ rearrangement and allows pre-TCR-independent survival of early αβ lineage thymocytes. Immunity 16: 869-879.
- Starr TK, Jameson SC, Hogquist KA (2003) Positive and negative selection of T cells. Annu Rev Immunol 21: 139-176.
- Hernandez JB, Newton RH, Walsh CM (2010) Life and death in the thymus -- cell death signaling during T cell development. Curr Opin Cell Biol 22: 865-871.
- Liu YJ (2001) Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell 106: 259-262.
- Hon H, Rucker EB 3rd, Hennighausen L, Jacob J (2004) bcl-xL is critical for dendritic cell survival in vivo. J Immunol 173: 4425-4432.
- Chen M, Huang L, Wang J (2007) Deficiency of Bim in dendritic cells contributes to overactivation of lymphocytes and autoimmunity. Blood 109: 4360-4367.
- Curtale G, Citarella F, Carissimi C, Goldoni M, Carucci N, et al. (2010) An emerging player in adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes. Blood 115: 265-273.
- Baumgart DC, Carding SR (2007) Inflammatory bowel disease: cause and immunobiology. Lancet 369: 1627-1640.
- Schulzke JD, Bojarski C, Zeissig S, Heller F, Gitter AH, et al. (2006) Disrupted barrier function through epithelial cell apoptosis. Ann N Y Acad Sci 1072: 288- 299.
- Yano T, Kurata S (2009) An unexpected twist for autophagy in Crohn’s disease. Nat Immunol 10: 134-136.
- Mirpuri J, Brazil JC, Berardinelli AJ, Nasr TR, Cooper K, et al. (2010) Commensal Escherichia coli reduces epithelial apoptosis through IFN-αAmediated induction of guanylate binding protein-1 in human and murine models of developing intestine. J Immunol 184: 7186-7195.
- Schnoor M, Betanzos A, Weber DA, Parkos CA (2009) Guanylate-binding protein-1 is expressed at tight junctions of intestinal epithelial cells in response to interferon-γ and regulates barrier function through effects on apoptosis. Mucosal Immunol 2: 33-42.
- Vallabhapurapu S, Karin M (2009) Regulation and function of NF-κB transcription factors in the immune system. Annu Rev Immunol 27: 693-733.
- Koch S, Nava S, Addis C, Kim W, Denning TL, et al. (2011) The Wnt antagonist Dkk1 regulates intestinal epithelial homeostasis and wound repair. Gastroenterology 141: 259-268.
- You JA, Nguyen AV, Albers CG, Lin F, Holcombe RF (2008) Wnt pathwayrelated gene expression in inflammatory bowel disease. Dig Dis Sci 53: 1013- 1019.
- Glover LE, Colgan SP (2011) Hypoxia and metabolic factors that influence inflammatory bowel disease pathogenesis. Gastroenterology 140: 1748-1755.
- Braun A, Treede I, Gotthardt D, Tietje A, Zahn A, et al. (2009) Alterations in phospholipid concentration and species composition of the intestinal mucus barrier in ulcerative colitis: a clue to pathogenesis. Inflamm Bowel Dis 15: 1705- 1720.
- Malemud CJ, Gillespie HJ (2005) The role of apoptosis in arthritis. Curr Rheum Rev 1: 131-142.
- Tang X (2007) Survival factors from activated accessory cells and their role in triggering autoimmune diseases. Curr Med Chem 14: 797-809.
- Brown KD, Claudio E, Siebenlist U (2008) The roles of the classical and alternative nuclear factor-κB pathways: Potential implications for autoimmunity and rheumatoid arthritis. Arthritis Res Ther 10: 212.
- Hutcheson J, Perlman H (2008) Apoptotic regulators and RA. Curr Rheum Rev 4: 254-258.
- Malemud CJ, Pearlman E (2009) Targeting JAK/STAT signaling pathway in inflammatory diseases. Curr Signal Transduct Ther 4: 201-221.
- Weinmann P, Moura RA, Caetano-Lopes JR, Pereira PA, Canhão H, et al. (2007) Delayed neutrophil apoptosis in early rheumatoid arthritis patients is abrogated by methotrexate therapy. Clin Exp Rheumatol 25: 885-887.
- Tracy D, Klareskog L, Sasso EH, Salfeld JG, Tak PP (2008) Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 117: 244-279.
- Jacques C, Gosset M, Berenbaum F, Gabay C (2006) The role of IL-1 and IL- 1Ra in joint inflammation and cartilage degradation. Vitam Horm 74: 371-403.
- Oldfield V, Dhillon S, Plosker GL (2010) Tocilizumab: a review of its use in rheumatoid arthritis. Drugs 69: 609-632.
- Caplan MS, Jilling T (2001) New concepts in necrotizing entercolitis. Curr Opin Pediatr 13: 111-115.
- Halpern MD, Clark JA, Saunders TA, Doelle SM, Hosseini DM, et al. (2006) Reduction of necrotizing enterocolitis with anti-TNF-α. Am J Physiol Gastrointest Liver Physiol 290: G757-G764.
- Heon Seo K, Ko HM, Kim HA, Choi JH, Jun Park S, et al. (2006) Platelet activating factor induces upregulation of antiapoptotic factors in a melanoma cell line through nuclear factor κB activation. Cancer Res 66: 4681-4686.
- Soliman A, Michelsen KS, Karahashi H, Lu J, Meng FJ, et al. (2010) Plateletactivating factor induces TLR4 expression in intestinal epithelial cells: Implication for the pathogenesis of necrotizing enterocolitis. PLoS One 5: e15044.
- Luo J, Lin ZB (2002) Advances of pharmacological effects of triterpenes from Ganoderma lucidum. Yao Xue Xue Bao 37: 574-578.
- Silva D (2003) Ganoderma lucidum (Reishi) in cancer treatment. Integr Cancer Ther 2: 358-364.
- Li CH, Chen PY, Chang UM, Kan LS, Fang WH, et al. (2005) Ganoderic acid X, a lanostanoid triterpene, inhibits topoisomerases and induces apoptosis in cancer cells. Life Sci 77: 252-265.
- Müller CI, Kumagai T, O’Kelly J, Seeram NP, Heber D, et al. (2006) Ganoderma lucidum causes apoptosis in leukemia, lymphoma and multiple myeloma cells. Leuk Res 30: 841-848.
- Calviño E, Manjón JL, Sancho P, Tejedor MC, Herráez A, et al. (2010) Ganoderma lucidum induced apoptosis in NB4 human leukemia cells: Involvement of Akt and Erk. J Ethnopharmacol 128: 71-78.
- Wang G, Zhao J, Liu J, Huang Y, Zhong JJ, et al. (2007) Enhancement of IL-2 and IFN-γ expression and NK cells activity involved in the anti-tumor effect of ganoderic acid Me in vivo. Int Immunopharmacol 7: 864-870.
- Yuen JW, Gohel MD, Ng CF (2011) The differential immunological activities of Ganoderma lucidum on human pre-cancerous uroepithelial cells. J. Ethnopharmacol 135: 711-718.
- Branno-Peppas L, Blanchette JO (2004) Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev 56: 1649-1659.