Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1995-05-24
1998-11-24
Achutamurthy, Ponnathapura
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
530300, 530324, 536 231, C12P 2106, A61K 3800, C07H 2104
Patent
active
058405240
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to chemotactic cytokine proteins, also known as chemokines. In particular, the present invention relates to a novel family of granulocyte chemotactic proteins.
BACKGROUND OF THE INVENTION
An essential feature of the immune system is the mechanism of neutrophil activation and phagocytosis, a process whereby foreign infecting particles are enveloped by phagocytes which function to excrete such particles from a cell. Chemotactic cytokines have been found to play a significant role in stimulating the migration of neutrophils to inflamed sites of infection, in order to kill invading microorganisms and allow phagocytosis to occur.
The cytokine family includes a number of structurally related proteins. Low molecular weight cytokines can be grouped into two subfamilies based on differences in protein structure and in chromosomal location of genes coding for the cytokine (Oppenheim et al., 1991, Annu. Rev. Immunol., 9:617; Wolpe et al., 1989, FASEB J., 3:2565). One subfamily of chemotactic proteins, the genes for which are located on human chromosome 17, possess two adjacent cysteine residues (C-C) in their amino-terminal protein sequence. Members of the other subfamily are encoded within human chromosome 4, and have a pair of cysteines separated by an amino acid (C-X-C). The first subfamily predominantly includes a number of monocyte chemotactic proteins (MCP) and the second subfamily is composed of granulocyte chemotactic proteins (GCP) including interleukin-8 (IL-8) and melanoma growth stimulating factor (GRO).
Some of the cytokines have been characterized by both in vitro and in vivo studies (Oppenheim and Wolpe, supra). For example, IL-8 has been reported to activate neutrophils leading to changes in cell shape, chemotaxis, degranulation, adherence to endothelium, increased vascular permeability and trans-endothelial emigration into tissues (Van Damme, 1991, Interleukin-8 and Related Molecules: The Cytokine Handbook, 201). GRO was first reported as a molecule involved in tumorigenesis (4). On the basis of its structural similarity with IL-8, GRO was later also characterized as a neutrophil activating protein (NAP). However, the biological functions of other identified proteins of this family, such as inflammatory protein-10 (IP-10), are not well understood (Oppenheim and Wolpe, supra).
Due to the importance of chemokines in the inflammatory process, it would be desirable to provide fully characterized proteins belonging to the chemokine family to enable the development of chemokine agonistic and antagonistic therapeutics for the treatment of inflammatory conditions.
Accordingly, it is an object of the present invention to provide novel chemotactic proteins.
SUMMARY OF THE INVENTION
A novel mammalian chemokine has been isolated and is designated herein granulocyte chemotactic protein-2 or GCP-2, a chemokine which is selectively chemotactic for granulocytes and, further, stimulates granulocytes to secrete proteases such as gelatinase B. Sequence-related variants of GCP-2 have also been identified. GCP-2 and such sequence-related variants of GCP-2 are herein referred to as GCP-2 proteins. Also encompassed by the term "GCP-2 proteins" are distinct peptide fragments of GCP-2.
The present invention thus provides, in one of its aspects, substantially pure mammalian granulocyte chemotactic protein-2 (GCP-2) proteins, collectively comprising mammalian GCP-2, sequence-related variants thereof and distinct peptide fragments.
In another aspect of the present invention, there is provided an isolated polynucleotide encoding a GCP-2 protein. There is also provided a recombinant vector having incorporated therein a polynucleotide encoding a GCP-2 protein, and a host cell that has been engineered genetically to produce a GCP-2 protein having incorporated expressibly therein heterologous DNA encoding said GCP-2 protein. Further, a recombinant method for producing a GCP-2 protein comprising the step of culturing cells which have incorporated expressibly therein a polynu
REFERENCES:
Walz, et al., Journal Exp. Med., vol. 174, Dec. 1991, pp. 1355-1362.
Goodman, et al., Journal Biol. Chem., vol. 266, No. 13, May 1991, pp. 8455-8463.
Goodman, et al., Biochemistry, vol. 31, No. 43, 1992, pp. 10483-10490.
Opdenakker, et al., Immunology Today, vol. 13, No. 11, 1992, pp. 463-464.
Rampart, et al., American Journal Pathology, vol. 135, No. 1, Jul. 1989, pp. 21-25.
Proost, et al., Biochemistry, vol. 32, No. 38, Sep. 1993, pp. 10170-10177.
Damme Jo Van
Proost Paul
Achutamurthy Ponnathapura
Park Hankyel T.
Stichting Rega VZW
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