PERSPECTIVE
Regulation of Eosinophil Viability by Cytokines

James G. Zangrilli

Division of Critical Care, Pulmonary, and Allergic and Immunologic Diseases, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania

Despite debate stimulated by recent human trials of interleukin (IL)-5 neutralization in asthma (1), there is a very large body of evidence supporting a pathogenic role for the eosinophil in allergic disease. In patients with asthma, airway and peripheral blood eosinophilia has been associated with the presence of a clinical late phase response, airway hyperreactivity, and symptom severity (2). In vitro-activated eosinophils and their products cause hyperreactivity of respiratory smooth muscle and epithelial dysfunction with frank exfoliation (5). Bronchial mucosal eosinophil infiltration was associated with disruption of the epithelial cell contacts in humans with asthma (9). The time-dependent and selective accumulation of circulating eosinophils into tissue compartments is very well-documented in allergen challenge models in the skin and respiratory track (2, 10, 11). Thus, eosinophil biology remains an area of intense interest in allergic inflammation. Research efforts here have focused on the investigation of selective adhesion and recruitment, and the determination of physiologic eosinophil viability factors. As mature eosinophils do not divide, and spontaneously undergo the apoptosis in the absence of specific viability-enhancing activities, the regulation of their survival should be a major determinant of the duration and severity of inflammation. Concerning eosinophil apoptosis, three major questions have occupied investigators: what are the principal eosinophil viability-enhancing activities during allergic inflammation in vivo, how are their signals transduced, and, finally, what genes are transcribed (or suppressed) that ultimately result in prolonged cellular viability? Although various Th2 cytokine family members, low molecular weight mediators, and specific tissue contacts demonstrate variable degrees of eosinophil viability enhancement in vitro, the hematopoietins IL-5 and granulocyte macrophage- colony-stimulating factor (GM-CSF) continue to enjoy the strongest in vitro and in vivo support in this capacity, and are a benchmark by which other potentially physiologic candidates should be compared.

IL-5 is the prototypic eosinophil viability-enhancing factor and, in contrast to GM-CSF, which can support the differentiation of multiple lineages, is specific for eosinophils (12). These cytokines act by inhibiting programmed cell death, and are extremely potent, with viability-enhancing activity detectable in the low picomolar range (13, 14). Neutralization of IL-5 activity in animal models substantially abrogated tissue eosinophilia after allergen challenge or during helminth infection, and suppressed airway hyperreactivity (15). Besides supporting viability, these cytokines also prime the eosinophil for certain functions, including chemotaxis, degranulation, LTC4 and superoxide synthesis, and antibody-dependent cytotoxicity (18). In human asthma, circulating IL-5 and GM-CSF levels were elevated in symptomatic asthmatics (19, 20). Both cytokines are increased in the airways of asthmatic subjects compared with nonasthmatic controls (21, 22), and are rapidly synthesized in the human airway following allergen challenge (23, 24). Indeed, IL-5 was shown to be the principal eosinophil viability-enhancing activity in BAL fluid obtained < 48 h after segmental lung challenge in allergic human subjects, with smaller contributions by GM-CSF (25). More prolonged kinetic studies of IL-5 and GM-CSF synthesis in the human airway, as well as sputum analysis in patients with symptomatic asthma, imply that IL-5 may be most important during initiation of an IgE-mediated inflammatory response, whereas GM-CSF may serve to maintain eosinophilia (24, 26). It is worthy of note that, although eosinophils have been shown to express both IL-5 and GM-CSF in certain settings in vivo, it would seem that GM-CSF is the preferred autocrine viability-enhancing factor, its release being consistently observed ex vivo from asthmatic subjects, as a result of stimulation with unrelated cytokines as discussed below, and under experimental adhesion conditions (27).

With such potent eosinophil survival activities in the form of IL-5 and GM-CSF, one wonders what need would there be for others? Indeed, IL-3 has well-documented comparable properties, and under experimental conditions, various other cytokines such as interferon-, IL-4, IL-9, IL-13 and tumor necrosis factor (TNF) will induce varying degrees of viability enhancement (31). It is likely that these seemingly redundant activities become important at different times and in different compartments such that the granulocyte is supported (and activated) by the coordinate activities of different mediators as it traverses the vessel and moves into the tissue. Synergy between these cytokines has been demonstrated in vitro (33, 34), and is likely to be important in vivo in the asthmatic airway, where multiple activities are expressed essentially simultaneously during the acute inflammatory response.

As eosinophils are truly programmed to die in the absence of these specific cytokine supports, there is great interest in how these surface signals are translated into prolonged survival. Research here has generally mirrored exciting recent developments in the areas of signal transduction and programmed cell death in the basic sciences. Transduction in the IL-3/IL-5/GM-CSF receptor system has been an area of intense investigation in engineered systems and noneosinophil cells revealing multiple activation pathways, with a limited but a growing body of literature relevant to eosinophils. Tyrosine phosphorylation was demonstrated to be essential to the anti-apoptotic activity of the IL-5-related cytokines toward eosinophils (36). As the high affinity IL-5/GM-CSF/IL-3 receptor consists of a common  and unique  subunit that has no intrinsic kinase activity, subsequent work has focused on identification of receptor-associated kinases. In eosinophils, investigators have shown the association and activation of the JAK2 kinase with subsequent activation of the Stat1  and Stat5, as well as Lyn and Syk tyrosine kinases and SHPT2 tyrosine phosphatase with ultimate activation of Ras/ERK kinase pathways (37). It is still difficult to assess the relative importance of a given pathway from the published data, as specific inhibition of various elements all seemed to abrogate the survival phenotype to some extent.

Finally, eosinophil viability factors have been examined in the context of recently described mammalian apoptotic pathways, including altered expression of the Bcl-2 family of proto-oncogenes and activation of the caspase cascade. The hypothesis that IL-5 may act by altering the balance of antiapoptotic to proapoptotic Bcl-2 homologs is attractive, but has yielded mixed results in experiments (43). At most, IL-5 caused tiny changes in certain antiapoptotic homologs (e.g., Bcl-2), but more generally appeared simply to maintain both antiapoptotic (e.g., Bax) and proapoptotic Bcl-2 homologs at basal levels. Thus, the evidence tends to go against these proteins as being major downstream effectors of the IL-5-related cytokines. In contrast, IL-5 had a profound effect upon the rate of spontaneous and stimulated activation of the caspase cascade in eosinophils. IL-5 completely blocked spontaneous and glucocorticoid-induced processing of the upstream activator caspase 8 and downstream effector caspase 3, and substantially slowed (but could not completely inhibit) that induced by directed Fas engagement (47). The level of this antagonism is an area of current research interest. Logical points of inhibition of the cascade would be at its initiation, either at the level of caspase 8 recruitment to the Fas receptor, or by stabilizing the mitochondrion and interfering with the formation of the recently described caspase 9/APAF complex (48). Alternatively, IL-5 might attenuate certain amplification loops such as Bid cleavage (49). Recent attention has focused on mitochondrial mechanisms in the initiation of spontaneous (i.e., factor withdrawal) and "chemically"-induced apoptosis, with the suggestion that they may be preeminent in eosinophils (50). IL-5 was shown to stabilize the mitochondrial membrane potential and inhibit caspase processing during conditions of factor withdrawal, but did so incompletely during Fas-mediated apoptosis (51, 52). In this light, IL-5 treatment was shown to stabilize Bax in the cytoplasmic compartment, preventing its translocation to the mitochondrion, thus suggesting a potential mechanism by which this cytokine may act (52).

Hoontrakoon and coworkers add to the mix in this issue of the AJRCMB by reporting substantial eosinophil viability-enhancing activity for IL-15 (53), a cytokine heretofore considered primarily in the context of lymphocyte and natural killer function (54). This effect could be conferred upon another common -chain-sharing cytokine IL-4 by coincubation with TNF-, confirming the results of others (33). As measurable amounts of IL-4 and TNF- are generated during an allergic airway response, and the authors demonstrate IL-15+ cells in the asthmatic airway, these results are of clinical interest. Similar to other eosinophil-active factors discussed above, the mechanism would appear to be the autocrine release of GM-CSF, and mediated through NF-B. A central role for NF-B in mediating programmed cell death has been suggested previously, and is an area of active research (55, 56). Integrating these observations with the established signaling pathways described above should keep "signal transductionists" occupied for some time.

	Footnotes

Address correspondence to: James G. Zangrilli, M.D., Rm. 805, College Building, 1025 Walnut Street, Philadelphia, PA 19107. E-mail: James. Zangrilli{at}mail.tju.edu

(Received in original form February 28, 2002).

	References

1. Leckie, M. J., A. ten Brinke, J. Khan, Z. Diamant, B. J. O'Connor, C. M. Walls, A. K. Mathur, H. C. Cowley, K. F. Chung, R. Djukanovic, T. T. Hansel, S. T. Holgate, P. J. Sterk, and P. J. Barnes. 2000. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356: 2144-2148 [Medline].

2. De Monchy, J. G., H. F. Kauffman, P. Venge, G. H. Koeter, H. M. Jansen, H. J. Sluiter, and K. De Vries. 1985. Bronchoalveolar eosinophilia during allergen-induced late asthmatic reactions. Am. Rev. Respir. Dis. 131: 373-376 [Medline].

3. Durham, S. R., and A. B. Kay. 1985. Eosinophils, bronchial hyperreactivity, and late-phase asthmatic reactions. Clin. Allergy 15: 411-418 [Medline].

4. Bousquet, J., P. Chanez, J. Y. Lacoste, G. Barneon, N. Ghavanian, I. Enander, P. Venge, S. Ahlstedt, J. Simony-Lafontaine, P. Godard, and F.-B. Michel. 1990. Eosinophilic inflammation in asthma. New Engl. J. Med. 323: 1033-1039 [Abstract].

5. Motojima, S., E. Frigas, D. A. Loegering, and G. J. Gleich. 1989. Toxicity of eosinophil cationic protein for guinea pig tracheal epithelium in vitro. Am. Rev. Respir. Dis. 139: 801-805 [Medline].

6. Yukawa, T., R. C. Read, C. Kroegel, A. Rutman, K. F. Chung, R. Wilson, P. J. Cole, and P. J. Barnes. 1990. The effect of activated eosinophils and neutrophils on guinea pig airway epithelium in vitro. Am. J. Respir. Cell Mol. Biol. 2: 341-353 .

7. Flavahan, N. A., N. R. Slifman, G. J. Gleich, and P. M. Vanhoutte. 1988. Human eosinophil major basic protein causes hyperreactivity of respiratory smooth muscle. Am. Rev. Respir. Dis. 138: 685-688 [Medline].

8. Rabe, K. F., N. M. Munoz, A. J. Vita, B. E. Morton, H. Magnussen, and A. R. Leff. 1994. Contraction of human bronchial smooth muscle caused by activated human eosinophils. Am. J. Physiol. 267: L326-L334 [Abstract/Free Full Text].

9. Ohashi, Y., S. Motojima, T. Fukuda, and S. Makino. 1992. Airway hyperresponsiveness, increased intracellular spaces of bronchial epithelium, and increased infiltration of eosinophils and lymphocytes in bronchial mucosa in asthma. Am. Rev. Respir. Dis. 145: 1469-1476 [Medline].

10. Kline, B. S., M. B. Cohen, and J. A. Rudolph. 1932. Histologic changes in allergic and non-allergic wheals. J. Immunol. 6: 531-541 .

11. Metzger, W. J., D. Zavala, H. B. Richerson, P. Moseley, P. Iwamota, M. Monick, K. Sjoerdsma, and G. W. Hunninghake. 1987. Local allergen challenge and bronchoalveolar lavage of allergic asthmatic lungs. Description of model and local airway inflammation. Am. Rev. Respir. Dis. 135: 433-440 [Medline].

12. Campbell, H. D., W. Q. Tucker, Y. Hort, M. E. Martinson, G. Mayo, E. J. Clutterbuck, C. J. Sanderson, and I. G. Young. 1987. Molecular cloning, nucleotide sequence, and expression of the gene encoding human eosinophil differentiation factor (interleukin 5). Proc. Natl Acad. Sci. USA. 84: 6629-6633 [Abstract/Free Full Text].

13. Yamaguchi, Y., T. Suda, S. Ohta, K. Tominaga, Y. Miura, and T. Kasahara. 1991. Analysis of the survival of mature human eosinophils: interleukin-5 prevents apoptosis in mature human eosinophils. Blood 78: 2542-2547 [Abstract/Free Full Text].

14. Wallen, N., H. Kita, D. Weiler, and G. Gleich. 1991. Glucocorticoids inhibit cytokine-mediated eosinophil survival. J. Immunol. 147: 3490-3495 [Abstract].

15. Coffman, R. L., B. W. Seymour, S. Hudak, J. Jackson, and D. Rennick. 1989. Antibody to interleukin-5 inhibits helminth-induced eosinophilia in mice. Science 245: 308-310 [Abstract/Free Full Text].

16. Gulbenkian, A. R., R. W. Egan, X. Fernandez, H. Jones, W. Kreutner, T. Kung, F. Payvandi, L. Sullivan, J. A. Zurcher, and A. S. Watnick. 1992. Interleukin-5 modulates eosinophil accumulation in the allergic guinea pig. Am. Rev. Respir. Dis. 146: 263-265 [Medline].

17. van Ooosterhout, A. J., A. R. Ladenius, H. F. Savelkoul, I. van Ark, K. C. Delsman, and F. P. Nijkamp. 1993. Effects of anti-IL-5 and IL-5 on airway hyperreactivity and eosinophils in guinea pigs. Am. Rev. Respir. Dis. 147: 548-552 [Medline].

18. Zangrilli, J. G., and S. P. Peters. 2000. Cytokines in allergic airway disease. In Asthma and Rhinitis, 2nd ed. W. W. Busse and S. T. Holgate, editors. Blackwell Science, Oxford. 577-596.

19. Brown, P. H., G. K. Crompton, and A. P. Greening. 1991. Proinflammatory cytokines in acute asthma. Lancet 338: 590-593 [Medline].

20. Corrigan, C. J., A. Haczku, V. Gemou-Engesaeth, S. Doi, Y. Kikuchi, K. Takatsu, S. R. Durham, and A. B. Kay. 1993. T lymphocyte activation in asthma is accompanied by increased serum concentrations of interleukin-5. Am. Rev. Respir. Dis. 147: 540-547 [Medline].

21. Robinson, D. S., Q. Hamid, S. Ying, A. Tsicopulos, J. Barkans, A. M. Bentley, C. Corrigan, S. R. Durham, and A. B. Kay. 1992. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. New Engl. J. Med. 326: 298-304 [Abstract].

22. Walker, C., E. Bode, L. Boer, T. T. Hansel, K. Blaser, and J.-C. Virchow. 1992. Allergic and Nonallergic asthmatics have distinct patterns of T-Cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am. Rev. Respir. Dis. 146: 109-115 [Medline].

23. Bentley, A. M., Q. Meng, D. S. Robinson, Q. Hamid, A. B. Kay, and S. R. Durham. 1993. Increase in activated T lymphocytes, eosinophils, and cytokine mRNA expression for interleukin-5 and granulocyte/macrophage colony stimulating factor in bronchial biopsies after allergen inhalation challenge in atopic asthmatics. Am. J. Respir. Cell Mol. Biol. 8: 35-42 .

24. Shaver, J. R., J. Zangrilli, S.-K. Cho, R. A. Cirelli, M. Pollice, A. T. Hastie, J. E. Fish, and S. P. Peters. 1997. Kinetics of the development and recovery of the lung from IgE-mediated inflammation: dissociation of pulmonary eosinophilia, lung injury, and eosinophil-active cytokines. Am. J. Respir. Crit. Care Med. 155: 442-448 [Abstract].

25. Ohnishi, T., H. Kita, D. Weiler, S. Sur, J. B. Sedgwick, W. J. Calhoun, W. W. Busse, J. S. Abrams, and G. J. Gleich. 1993. IL-5 is the predominant eosinophil-active cytokine in the antigen-induced pulmonary late-phase reaction. Am. Rev. Respir. Dis. 147: 901-907 [Medline].

26. Adachi, T., S. Motojima, A. Hirata, T. Fukuda, and S. Makino. 1995. Eosinophil viability-enhancing activity in sputum from patients with bronchial asthma, Contributions of interleukin-5 and granulocyte/macrophage colony-stimulating factor. Am. J. Respir. Crit. Care Med. 151: 618-623 [Abstract].

27. Kankaanranta, H., M. A. Lindsay, M. A. Giembycz, X. Zhang, E. Moilanen, and P. J. Barnes. 2000. Delayed eosinophil apoptosis in asthma. J. Allergy Clin. Immunol. 106: 77-83 [Medline].

28. Yamamoto, H., J. B. Sedgwick, R. F. Vrtis, and W. W. Busse. 2000. The effect of transendothelial migration on eosinophil function. Am. J. Respir. Cell Mol. Biol. 23: 379-388 [Abstract/Free Full Text].

29. Meerschaert, J., R. F. Vrtis, Y. Shikama, J. B. Sedgwick, W. W. Busse, and D. F. Mosher. 1999. Engagement of alpha4beta7 integrins by monoclonal antibodies or ligands enhances survival of human eosinophils in vitro. J. Immunol. 163: 6217-6227 [Abstract/Free Full Text].

30. Anwar, A. R. F., R. Moqbel, G. M. Walsh, A. B. Kay, and A. J. Wardlaw. 1993. Adhesion to fibronectin prolongs eosinophil survival. J. Exp. Med. 177: 839-843 [Abstract/Free Full Text].

31. Valerius, T., R. Repp, J. R. Kalden, and E. Platzer. 1990. Effects of IFN on human eosinophils in comparison with other cytokines. A novel class of eosinophil activators with delayed onset of action. J. Immunol. 145: 2950-2958 [Abstract].

32. Luttmann, W., B. Knoechel, M. Foerster, H. Matthys, J. C. Virchow Jr., and C. Kroegel. 1996. Activation of human eosinophils by IL-13. Induction of CD69 surface antigen, its relationship to messenger RNA expression, and promotion of cellular viability. J. Immunol. 157: 1678-1683 [Abstract].

33. Luttmann, W., T. Matthiesen, H. Matthys, and J. C. Virchow Jr.. 1999. Synergistic effects of interleukin-4 or interleukin-13 and tumor necrosis factor-alpha on eosinophil activation in vitro. Am. J. Respir. Cell Mol. Biol. 20: 474-480 [Abstract/Free Full Text].

34. Gounni, A. S., B. Gregory, E. Nutku, F. Aris, K. Latifa, E. Minshall, J. North, J. Tavernier, R. Levit, N. Nicolaides, D. Robinson, and Q. Hamid. 2000. Interleukin-9 enhances interleukin-5 receptor expression, differentiation, and survival of human eosinophils. Blood 96: 2163-2171 [Abstract/Free Full Text].

35. Temkin, V., and F. Levi-Schaffer. 2001. Mechanism of tumour necrosis factor alpha mediated eosinophil survival. Cytokine 15: 20-26 [Medline].

36. Yousefi, S., D. R. Green, K. Blaser, and H. U. Simon. 1994. Protein-tyrosine phosphorylation regulates apoptosis in human eosinophils and neutrophils. Proc. Natl. Acad. Sci. USA 91: 10868-10872 [Abstract/Free Full Text].

37. van der Bruggen, T., E. Caldenhoven, D. Kanters, P. Coffer, J. A. Raaijmakers, J. W. Lammers, and L. Koenderman. 1995. Interleukin-5 signaling in human eosinophils involves JAK2 tyrosine kinase and Stat1 alpha. Blood 85: 1442-1448 [Abstract/Free Full Text].

38. Pazdrak, K., D. Schreiber, P. Forsythe, L. Justement, and R. Alam. 1995. The intracellular signal transduction mechanism of interleukin 5 in eosinophils: the involvement of lyn tyrosine kinase and the Ras-Raf-1-MEK-microtubule-associated protein kinase pathway. J. Exp. Med. 181: 1827-1834 [Abstract/Free Full Text].

39. Pazdrak, K., T. Adachi, and R. Alam. 1997. Src homology 2 protein tyrosine phosphatase (SHPTP2)/Src homology 2 phosphatase 2 (SHP2) tyrosine phosphatase is a positive regulator of the interleukin 5 receptor signal transduction pathways leading to the prolongation of eosinophil survival. J. Exp. Med. 186: 561-568 [Abstract/Free Full Text].

40. Yousefi, S., D. C. Hoessli, K. Blaser, G. B. Mills, and H. U. Simon. 1996. Requirement of Lyn and Syk tyrosine kinases for the prevention of apoptosis by cytokines in human eosinophils. J. Exp. Med. 183: 1407-1414 [Abstract/Free Full Text].

41. Hall, D. J., J. Cui, M. E. Bates, B. A. Stout, L. Koenderman, P. J. Coffer, and P. J. Bertics. 2001. Transduction of a dominant-negative H-Ras into human eosinophils attenuates extracellular signal-regulated kinase activation and interleukin-5-mediated cell viability. Blood 98: 2014-2021 [Abstract/Free Full Text].

42. Bhattacharya, S., B. A. Stout, M. E. Bates, P. J. Bertics, and J. S. Malter. 2001. Granulocyte macrophage colony-stimulating factor and interleukin-5 activate STAT5 and induce CIS1 mRNA in human peripheral blood eosinophils. Am. J. Respir. Cell Mol. Biol. 24: 312-316 [Abstract/Free Full Text].

43. Dewson, G., G. M. Walsh, and A. J. Wardlaw. 1999. Expression of Bcl-2 and Its Homologues in Human Eosinophils. Am. J. Respir. Cell Mol. Biol. 20: 720-728 [Abstract/Free Full Text].

44. Ochiai, K., M. Kagami, R. Matsumura, and H. Tomioka. 1997. IL-5 but not interferon-gamma (IFN-gamma) inhibits eosinophil apoptosis by up-regulation of bcl-2 expression. Clin. Exp. Immunol. 107: 198-204 [Medline].

45. Druilhe, A., M. Arock, L. Le Goff, and M. Pretolani. 1998. Human eosinophils express Bcl-2 family proteins: modulation of Mcl-1 expression by IFN-gamma. Am. J. Respir. Cell Mol. Biol. 18: 315-322 [Abstract/Free Full Text].

46. Dibbert, B., I. Daigle, D. Braun, C. Schranz, M. Weber, K. Blaser, U. Zangemeister-Wittke, A. N. Akbar, and H. U. Simon. 1998. Role for Bcl-xL in delayed eosinophil apoptosis mediated by granulocyte-macrophage colony-stimulating factor and interleukin-5. Blood 92: 778-783 [Abstract/Free Full Text].

47. Zangrilli, J., N. Robertson, A. Shetty, J. Wu, A. Hastie, J. E. Fish, G. Litwack, and S. P. Peters. 2000. Effect of IL-5, glucocorticoid, and Fas ligation on Bcl-2 homologue expression and caspase activation in circulating human eosinophils. Clin. Exp. Immunol. 120: 12-21 [Medline].

48. Li, P., D. Nijhawan, I. Budihardjo, S. M. Srinivasula, M. Ahmad, E. S. Alnemri, and X. Wang. 1997. Cytochrome c and dATP-dependent formation of Apaf-1/ caspase-9 complex initiates an apoptotic protease cascade. Cell 91: 479-489 [Medline].

49. Li, H., H. Zhu, C. J. Xu, and J. Yuan. 1998. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94: 491-501 [Medline].

50. Peachman, K. K., D. S. Lyles, and D. A. Bass. 2001. Mitochondria in eosinophils: functional role in apoptosis but not respiration. Proc. Natl. Acad. Sci. USA 98: 1717-1722 [Abstract/Free Full Text].

51. Letuve, S., A. Druilhe, M. Grandsaigne, M. Aubier, and M. Pretolani. 2001. Involvement of caspases and of mitochondria in Fas ligation-induced eosinophil apoptosis: modulation by interleukin-5 and interferon-gamma. J. Leukoc. Biol. 70: 767-775 [Abstract/Free Full Text].

52. Dewson, G., G. M. Cohen, and A. J. Wardlaw. 2001. Interleukin-5 inhibits translocation of Bax to the mitochondria, cytochrome c release, and activation of caspases in human eosinophils. Blood 98: 2239-2247 [Abstract/Free Full Text].

53. Hoontrakoon, R., H. W. Chu, S. J. Gardai, S. E. Wenzel, P. McDonald, V. A. Fadok, P. M. Henson, and D. L. Bratton. 2002. Interleukin-15 inhibits spontaneous apoptosis in human eosinophils via autocrine production of granulocyte-colony stimulating factor and nuclear factor-B activation. Am. J. Respir. Cell Mol. Biol. 26: 404-412 [Abstract/Free Full Text].

54. Waldmann, T. A., and Y. Tagaya. 1999. The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens. Ann. Rev. Immunol. 17: 19-49 [Medline].

55. Baeuerle, P. A., and D. Baltimore. 1996. NF-kappa B: ten years after. Cell 87: 13-20 [Medline].

56. You, Z., H. Ouyang, D. Lopatin, P. J. Polver, and C. Y. Wang. 2001. Nuclear factor-kappa B-inducible death effector domain-containing protein suppresses tumor necrosis factor-mediated apoptosis by inhibiting caspase-8 activity. J. Biol. Chem. 276: 26398-26404 [Abstract/Free Full Text].