Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1998-12-07
2001-04-03
Kemmerer, Elizabeth (Department: 1646)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C436S501000, C530S387100, C530S388100
Reexamination Certificate
active
06210905
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a protein, TSG-6, inducible in connective tissue cells by tumor necrosis factor or interleukin-1, DNA and mRNA encoding the TSG-6 protein, functional derivatives of the protein, antibodies specific to the protein, methods of producing the protein and DNA, and uses of the protein, DNA, mRNA, peptides and antibodies.
2. Description of the Background Art
Tumor necrosis factor (TNF) is a powerful pleiotropic cytokine important in host defenses against tumors and infectious agents. TNF has also been implicated in the pathology of some neoplastic diseases, infections and autoimmune disorders. Most biological actions of TNF can be attributed to the triggering of complex genetic programs in the target cells. Several genes activated by TNF have been identified but many more require characterization.
General Properties of TNF
TNF (also termed TNF-&agr; and cachectin) is a protein produced by activated monocytes/macrophages which was originally detected in the serum of animals injected sequentially with a bacterial vaccine (bacillus Calmette-Guerin, BCG) and endotoxin (Carswell, E. A. et al.,
Proc. Natl. Acad. Sci. USA
72:3666 (1975)). TNF is structurally and functionally related to a cytokine produced by activated T lymphocytes which was originally termed lymphotoxin (LT) and is also known as TNF-&bgr; (Aggarwal, B. B. et al.,
J. Biol. Chem.
260:2334 (1985); Williams, T. W. et al.,
Nature
219:1076 (1968); Ruddle, N. H. et al.,
J. Exp. Med.
128:1267 (1968); Spies, T. et al.,
Proc. Natl. Acad. Sci. USA
83:8699 (1986); Gray, P. W. et al.,
Nature
312:721 (1984); Pennica, D. W. et al.,
Nature
312:724 (1984)). The genes encoding TNF and LT are linked, and are near the HLA-DR locus on the short arm of human chromosome 6 (Spies, T. et al., supra). TNF and LT bind to common cell surface receptors (Aggarwal, B. B. et al.,
Nature
318:665 (1985)).
Natural human TNF is a 157 amino acid, non-glycosylated protein with a molecular weight of approximately 17 kDa under denaturing conditions. The mature molecule is derived from a precursor (pre-TNF) which contains 76 additional amino acids at the N-terminus (Pennica, D. W. et al., supra). The expression of the gene encoding TNF is not limited to cells of the monocyte/macrophage family. Several human non-monocytic tumor cell lines were shown to produce TNF (Rubin, B. Y. et al.,
J. Exp. Med.
164:1350 (1986); Spriggs, D. et al.,
Proc. Natl. Acad. Sci. USA
84:6563 (1987)). TNF is also produced by CD4
+
and CD8
+
peripheral blood T lymphocytes, and by various cultured T and B cell lines (Cuturi, M. C., et al.,
J. Exp. Med.
165:1581 (1987); Sung, S.-S. J. et al.,
J. Exp. Med.
168:1539 (1988)).
Accumulating evidence indicates that TNF is a regulatory cytokine with pleiotropic biological activities. These activities include: inhibition of lipoprotein lipase synthesis (“cachectin” activity) (Beutler, B. et al.,
Nature
316:552 (1985)), activation of polymorphonuclear leukocytes (Klebanoff, S. J. et al.,
J. Immunol.
136:4220 (1986); Perussia, B., et al.,
J. Immunol.
138:765 (1987)), inhibition of cell growth or stimulation of cell growth (Vilcek, J. et al.,
J. Exp. Med.
163:632 (1986); Sugarman, B. J. et al.,
Science
230:943 (1985); Lachman, L. B. et al.,
J. Immunol.
138:2913 (1987)), cytotoxic action on certain transformed cell types (Lachman, L. B. et al., supra; Darzynkiewicz, Z. et al.,
Canc. Res.
44:83 (1984)), antiviral activity (Kohase, M. et al.,
Cell
45:659 (1986); Wong, G. H. W. et al.,
Nature
323:819 (1986)), stimulation of bone resorption (Bertolini, D. R. et al.,
Nature
319:516 (1986); Saklatvala, J.,
Nature
322:547 (1986)), stimulation of collagenase and prostaglandin E2 production (Dayer, J.-M. et al.,
J. Exp. Med.
162:2163 (1985)), and other actions. For reviews of TNF, see Beutler, B. et al.,
Nature
320:584 (1986), Old, L. J.,
Science
230:630 (1986), and Le, J. et al.,
Lab. Invest.
56:234 (1987).
TNF also has immunoregulatory actions, including activation of T cells (Yokota, S. et al.,
J. Immunol.
140:531 (1988)), B cells (Kehrl, J. H. et al.,
J. Exp. Med.
166:786 (1987)), monocytes (Philip, R. et al.,
Nature
323:86 (1986)), thymocytes (Ranges, G. E. et al.,
J. Exp. Med.
167:1472 (1988)), and stimulation of the cell-surface expression of major histocompatibility complex (MHC) class I and class II molecules (Collins, T. et al.,
Proc. Natl. Acad. Sci. USA
83:446 (1986); Pujol-Borrell, R. et al.,
Nature
326:304 (1987)).
TNF also has various pro-inflammatory actions which result in tissue injury, such as induction of procoagulant activity on vascular endothelial cells (Pober, J. S. et al., J. Immunol. 136, 1680, 1986)), increased adherence of neutrophils and lymphocytes (Pober, J. S. et al.,
J. Immunol.
138:3319 (1987)), and stimulation of the release of platelet activating factor (PAF) from macrophages, neutrophils and vascular endothelial cells (Camussi, G. et al.,
J. Exp. Med.
166:1390 (1987)). Recent evidence implicates TNF in the pathogenesis of many infections (Cerami, A. et al.,
Immunol. Today
9:28 (1988)), immune disorders (Piguet, P.-F. et al.,
J. Exp. Med.
166:1280 (1987)), and in cachexia accompanying some malignancies (Oliff, A. et al.,
Cell
50:555 (1987)). Michie, H. R. et al.,
Br. J. Surg.
76:670-671 (1989), reviewed evidence that TNF is the principal mediator associated with the pathological changes of severe sepsis.
TNF also has activity associated with growth and differentiation of hemopoietic precursor cells (Murphy, M. et al.,
J. Exp. Med.
164:263 (1986); Broxmeyer, H. E. et al.,
J. Immunol.
136:4487 (1986)); some of these actions may be indirect, and are thought to be mediated through the stimulation of production of granulocyte-macrophage colony stimulating factor (GM-CSF) (Munker, R. et al.,
Nature
323:79 (1986)) and other hemopoietic growth factors (Zucali, J. R. et al.,
J. Immunol.
140:840 (1988)).
Regulation of Gene Expression by TNF
It is, therefore, apparent that TNF is an extremely “versatile” and clinically significant cytokine. Most of its actions are likely to be mediated by the activation or inactivation of specific genes in the cells upon which it acts. One exception to this mode of action is the rapid cytotoxic effect of TNF on certain target cells; this effect is augmented by inhibitors of RNA or protein synthesis and does not appear to depend on the modulation of gene expression (Matthews, N.,
Br. J. Cancer
48:405 (1983)). Many specific gene products have been shown to be up-regulated in TNF-treated cells, some of which are discussed below.
Among the first examples of TNF-modulated gene expression was the demonstration that TNF treatment induced an increase in MHC class I mRNA levels and in surface expression of the MHC class I glycoproteins in human vascular endothelial cells (HUVEC) and normal skin fibroblasts (Collins, T. et al., supra). A partial list of other molecules (or genes) induced by TNF appears in Table 1, below. It is interesting to note that TNF is an autoregulatory cytokine, since exogenously added TNF increases TNF synthesis in monocytes and monocytic cell lines (Philip, R. et al.,
Nature
323:86 (1986); Schmid, J. et al.,
J. Immunol.
139:250 (1987)).
TABLE 1
GENES AND PROTEINS INDUCED BY TUMOR NECROSIS FACTOR
Protein or Gene
Ref
Cell Type
Leukocyte adhesion protein H4/18
HUVEC
(1)
Platelet-derived growth factor
HUVEC and some tumor
(2)
(PDGF)
cell lines
IL-6 (IFN-&bgr; or BSF-2)
Human skin fibroblasts
(3)
HLA-DR
Human tumor cell lines
(4)
Collagenase
Synovial cells and
(5)
skin fibroblasts
2′-5′ oligoadenylate synthetase
Tumor cell lines
(6)
c-myc and c-fos oncogenes
Human skin fibroblasts
(7)
Epidermal growth factor receptor
Human skin fibroblasts
(8)
Tissue factor
HUVEC
(9)
ICAM-1 and ELAM-1
HUVEC
(10)
Plasminogen activator inhibitors
HT1080 cell line
(11)
1 and 2 (PAI-1 and PAI-2)
Synthesis of 36 kDa and 42 kDa
Human skin fibroblasts
(12)
(=PAI-2) proteins
Superoxide Dismutase (MnSOD) gene
Human tum
Lee Tae Ho
Vilcek Jan
Wisniewski Hans-Georg
Browdy and Neimark
Kemmerer Elizabeth
New York University
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