Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Reexamination Certificate
1997-03-13
2002-07-09
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
C424S144100, C424S145100
Reexamination Certificate
active
06416753
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention is in the field of molecular biology as related to the control of programmed cell death.
2. Description of the Background Art
Programmed Cell Death
Apoptosis, also referred to as programmed cell death or regulated cell death, is a process by which organisms eliminate unwanted cells. Such cell death occurs as a normal aspect of animal development as well as in tissue homeostasis and aging (Glucksmann, A.,
Biol. Rev. Cambridge Philos. Soc.
26:59-86 (1950); Ellis et al.,
Dev.
112:591-603 (1991); Vaux et al.,
Cell
76:777-779 (1994)). Programmed cell death can also act to regulate cell number, to facilitate morphogenesis, to remove harmful or otherwise abnormal cells and to eliminate cells that have already performed their function. Additionally, programmed cell death is believed to occur in response to various physiological stresses such as hypoxia or ischemia. The morphological characteristics of apoptosis include plasma membrane blebbing, condensation of nucleoplasm and cytoplasm and degradation of chromosomal DNA at inter-nucleosomal intervals. (Wyllie, A. H., in
Cell Death in Biology and Pathology,
Bowen and Lockshin, eds., Chapman and Hall (1981), pp. 9-34).
Apoptosis is achieved through an endogenous mechanism of cellular suicide (Wyllie, A. H., in
Cell Death in Biology and Pathology,
Bowen and Lockshin, eds., Chapman and Hall (1981), pp. 9-34) and occurs when a cell activates its internally encoded suicide program as a result of either internal or external signals. The suicide program is executed through the activation of a carefully regulated genetic program (Wylie, A. H., et al.,
Int. Rev. Cyt.
68: 251 (1980); Ellis, R. E., etal.,
Ann. Rev. Cell Bio.
7:663 (1991)). In many cases, gene expression appears to be required, since cell death can be prevented by inhibitors of RNA or protein synthesis (Cohen et al,
J. Immunol.
32:38-42 (1984); Stanisic et al.,
Invest. Urol.
16:19-22 (1978); Martin et al.,
J. Cell Biol.
106:829-844 (1988). A genetic pathway of programmed cell death was first identified in the nematode
C. elegans.
In this worm, the products of ced-3 and ced-4 genes carry out the program of cellular suicide (Yuan & Horvitz,
Dev. Bio.
138: 33 (1990)).
Interleukin-1&bgr; Converting Enzyme
The mammalian homologue of the ced-3 gene product is interleukin-1&bgr; converting enzyme (ICE), a cysteine protease responsible for the activation of interleukin-1&bgr; (IL-1&bgr;) (Thomberry, N. A., etal.,
Nature
356: 768 (1992); Yuan, J., et al.,
Cell
75: 641 (1993); Miura, M., et al.,
Cell
75: 653 (1993)). The Ice gene is a member of a family of genes. The mammalian ICE/Ced-3 family now includes at least six members: ICE, ICH-1/NEDD2, CPP32/Yama/Apopain, TX/ICEreIII/ICH-2, ICEreIIII and MCH2 (Yuan et al.,
Cell
75:641-652 (1993); Wang et al.,
Cell
78:739-750 (1994); Kumar et al.,
Genes Dev.
8:1613-1626 (1994); Fernandes-Alnerrni et al.,
J. Biol. Chem.
269:30761-30764 (1994); Tewari, M., et al.,
Cell
81:801-809 (1995); Nicholson, D., et al.,
Nature
376:37-43 (1995); Faucheu, C., et al.,
J. Biol. Chem.
269:30761-30764 (1994); Munday, N. A., et al.,
J. Biol. Chem.
270:15870-15876 (1995); Kamens, J., et al.,
J. Biol. Chem.
270:15250-15256 (1995); Femandes-Alnermi, et al.,
Canc. Res
55:2737-2742 (1994)).
Interleukin-1&bgr; converting enzyme (ICE) is a substrate-specific cysteine protease that cleaves the inactive 31 KD prointerleukin-1&bgr; at Asp
116
-Ala
117
, releasing a carboxy-terminal 153 amino-acid peptide to produce the mature 17.5 kD interleukin-1&bgr; (IL1&bgr;) (Kostura et al.,
Proc. Natl. Acad. Sci., USA
86:5227-5231 (1989); Black et al.,
FEBS Lett.
247:386-390 (1989); Cerretti et al.,
Science
256:97-100 (1992); Thomberry et al.,
Nature
356:768-774 (1992)). Since this is member of a family of proteases whose active site cysteine residue is essential for ICE-mediated apoptosis, their proteolytic activity appears critical in mediating cell death (Miura et al.,
J. Cell
75:653-660 (1993)). IL1&bgr; is also a cytokine involved in mediating a wide range of biological responses including inflammation, septic shock, wound healing, hematopoiesis and growth of certain leukemias (Dinarello, C. A.,
Blood
77:1627-1652 (1991); diGiovine et al.,
Today
11:13 (1990)).
A specific inhibitor of ICE, the crmA gene product of cowpox virus, prevents the proteolytic activation of IL-1&bgr; (Ray et al.,
Cell
69:597-604 (1992)) and also inhibits host inflammatory response (Ray et al., Cell 69:597-604 (1992)). Cowpox virus carrying a deleted crmA, gene is unable to suppress the inflammatory response of chick embryos, resulting in a reduction in the number of virus-infected cells and less damage to the host (Palumbo et al.,
Virology
171:262-273 (1989)). This observation indicates the importance of ICE in bringing about the inflammatory response.
It has also been shown that ICE overexpression induces apoptosis, and that mature IL-1&bgr; is released during cell death (Miura, M., et al.,
Cell
75: 653 (1993); Miura, M., et al.,
Proc. Natl. Acad. Sci. USA.
92:8318-8322, (1995). The cowpox virus gene product CrmA, a member of the serpin family and an inhibitor of ICE also prevents apoptosis (Miura, M., et al.,
Cell
75: 653 (1993); Miura, M., et al.,
Proc. Natl. Acad. Sci. USA.
(In press); Ray, C. A., et al.,
Cell
69: 597 (1992); Gagliardini, V., et al.,
Science
263: 826 (1993); Boudreau, N., et al.,
Science
267: 891 (1995); Enari, M., et al.,
Nature
375: 78 (1995); Los, M., et al.,
Nature
375: 81 (1995)). In addition, the ability of CrmA to inhibit apoptosis correlates with its ability to inhibit mature IL-1&bgr; production. Recent reports indicate that tumor necrosis factor-&agr; TNF-&agr;) induced apoptosis is mediated through a CrmA-inhibitable pathway suggesting involvement of the ICE family (Tewary, M., et al.,
J. Biol. Chem
270: 3255 (1995); Hsu, H., et al.,
Cell
81: 495 (1995); Miura, M., et al.,
Natl. Acad Sci. U.S.A.
(In press)).
While the critical role of the ICE family in cell death is well accepted, the function of mature IL-1&bgr; in apoptosis is controversial. IL-1&bgr; has been shown to induce apoptosis in some systems (Onozaki et al.,
Immun
135:3962-3968 (1985); Ankarcrona etal.,
Exp. Cell Res.
213:172-177 (1994); Fratelli, M., etal.,
Blood
85:3532-3637 (1995)), and to prevent it in others (Belizario & Dinarello,
Cancer Res.
51:2379-2385 (1991); Strijbos & Rothwell,
J. Neurosci.
15:3468-3474 (1995)). Mature IL-1&bgr; has not only been detected in the media of TNF-&agr; treated apoptotic fibroblasts, but also in the media of macrophages undergoing apoptosis following
Shigella flexneri
infection (Zychlinsky, A., et al.,
J. Clin. Invest.
94: 1328 (1994)). The detection of mature IL-1&bgr; release during apoptosis provides strong evidence for ICE itself being activated in cell death, since in-vivo ICE is the major (if not the only) protease responsible for the processing of proIL-1&bgr; as demonstrated in ICE deficient mice (Li, P., et al.,
Cell
80: 401 (1995); (Kuida, K., et al.,
Science
267: 2000 (1995)).
Tumor Necrosis Factor
Tumor necrosis factor-&agr; (TNF-&agr;) is a pleiotropic tumoricidal cytokine (Tracey, K. J. et al.,
Ann. Rev. Cell. Biol.
9:317-343 (1993)). One of the striking functions of TNF-&agr; is to induce apoptosis of transformed cells. In the case of non-transformed cells, TNF&agr; can also induce apoptosis in the presence of metabolic inhibitors (Tracey, K. J., et al.,
Ann. Rev. Cell. Biol.
9:317-343 (1993). Apoptosis induced by TNF-&agr; is also suppressed by bcl-2.
One of the most extensively studied functions of TNF-&agr; is its cytotoxicity on a wide variety of tumor cell lines in vitro (Laster, S. M. et al.,
J. Immunol.
141:2629-2634 (1988)). However, the mechanism of cell death induced by TNF has been largely unknown. HeLa cells express predominantly p55 TNF receptor which is thought to be responsible for cell death signaling (Englemann, H. et al.,
J. Biol. Chem.
265:14497-14504 (1990);
Friedlander Robert
Yuan Junying
Carlson Karen Cochrane
Sterne Kessler Goldstein & Fox P.L.L.C.
The General Hospital Corporation
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