Polynucleotides encoding a novel interleukin receptor termed...

Details Polynucleotides encoding a novel interleukin receptor termed... Polynucleotides encoding a novel interleukin receptor termed...

1998-09-16

2003-10-21

Spector, Lorraine (Department: 1646)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

C435S320100, C435S325000, C435S252300, C435S006120, C536S023500

Reexamination Certificate

active

06635443

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel human gene encoding a polypeptide which is a member of the interleukin (IL)-17 receptor family. More specifically, isolated nucleic acid molecules are provided encoding a human polypeptide named Interleukin 17-Receptor-Like Protein, hereinafter referred to as IL17RLP. IL17RLP polypeptides are also provided, as are vectors, host cells and recombinant methods for producing the same. Also provided are diagnostic methods for detecting disorders related to the immune system and therapeutic methods for treating such disorders. The invention further relates to screening methods for identifying agonists and antagonists of IL17RLP activity.
BACKGROUND OF THE INVENTION
Cytokines typically exert their respective biochemical and physiological effects by binding to specific receptor molecules. Receptor binding will then stimulate specific signal transduction pathways (Kishimoto, T., et al.,
Cell
76:253-262 (1994). The specific interactions of cytokines with their receptors are often the primary regulators of a wide variety of cellular process including activation, proliferation, and differentiation (Arai, K.-I, et al.,
Ann. Rev. Biochem
. 59:783-836 (1990); Paul, W. and Seder, R.,
Cell
76:241-251 (1994)).
Human interleukin (IL)-17 was only recently identified. IL-17 is a 155 amino acid polypeptide which was molecularly cloned from a CD4+ T-cell cDNA library (Yao, Z., et al.,
J. Immunol
. 155:5483-5486 (1995)). The IL-17 polypeptide contains an N-terminal signal peptide and contains approximately 72% identity at the amino acid level with a T-cell trophic herpesvirus saimiri (HVS) gene designated HVS13. High levels of IL-17 are secreted from CD4-positive primary peripheral blood leukocytes (PBL) upon stimulation (Yao, Z., et al.,
Immunity
3:811-821 (1995)). Treatment of fibroblasts with IL-17, HVS 13, or another murine homologue, designated CTLA8, activate signal transduction pathways and result in the stimulation of the NF-&kgr;B transcription factor family, the secretion of IL-6, and the costimulation of T-cell proliferation (Yao, Z., et al.,
Immunity
3:811-821 (1995)).
An HVS13-Fc fusion protein was used to isolate a murine IL-17 receptor molecule which does not appear to belong to any of the previously described cytokine receptor families (Yao, Z., et al.,
Immunity
3:811-821 (1995)). The murine IL-17 receptor (mIL-17R) is predicted to encode a type I transmembrane protein of 864 amino acids with an apparent molecular mass of 97.8 kDa. mIL-17R is predicted to possess an N-terminal signal peptide with a cleavage site between alanine-31 and serine-32. The molecule also contains a 291 amino acid extracellular domain, a 21 amino acid transmembrane domain, and a 521 amino acid cytoplasmic tail. A soluble recombinant IL- 17R molecule consisting of 323 amino acids of the extracellular domain of IL-17R fused to the Fc portion of human IgGl was able to significantly inhibit IL-17-induced IL-6 production by murine NIH-3T3 cells (supra).
Interestingly, the expression of the IL-17 gene is highly restricted. It is typically observed primarily in activated T-lymphocyte memory cells (Broxmeyer, H.
J. Exp. Med
. 183:2411-2415 (1996); Fossiez, F., et al.,
J. Exp. Med
. 183:2593-2603 (1996)). Conversely, the IL-17 receptor appears to be expressed in a large number of cells and tissues including (Rouvier, E., et al.,
J. Immunol
. 150:5445-5456 (1993); Yao, Z., et al.,
J. Immunol
. 155:5483-5486 (1995)). It remains to be seen, however, if IL-17 itself can play an autocrine role in the expression of IL-17. IL-17 has been implicated as a causitive agent in the expression of IL-6, IL-8, G-CSF, Prostaglandin E (PGE
2
), and intracellular adhesion molecule (ICAM)-1 (Fossiez, F., supra; Yao, Z., et al.,
Immunity
3:811-821 (1995)). Each of these molecules possesses highly relevent and potentially therapeutically valuable properties. For instance, IL-6 is involved in the regulation of hematopoietic stem and progenitor cell growth and expansion (Ikebuchi, K., et al.,
Proc. Natl. Acad. Sci. USA
84:9035-9039 (1987); Gentile, P. and Broxmeyer, H. E.
Ann. N.Y Acad. Sci. USA
628:74-83 (1991)). IL-8 exhibits a myelosuppressive activity for stem and immature subsets of myeloid progenitors (Broxmeyer, H. E., et al.,
Ann. Hematol
. 71:235-246 (1995); Daly, T. J., et al.,
J. Biol. Chem
. 270:23282-23292 (1995)). G-CSF acts early and late to activate and stimulate hematopoiesis in general (more specifically, neutrophil hematopoiesis) while PGE
2
enhances erythropoiesis, suppresses lymphopoiesis and myelopoiesis in general, and strongly suppresses monocytopoiesis (Broxmeyer, H. E.
Amer. J Ped. Hematol./Oncol
. 14:22-30 (1992); Broxmeyer, H. E. and Williams, D. E.
CRC Crit. Rev. Oncol./Hematol
. 8:173-226 (1988)).
IL-17 receptor appears to be structurally unrelated to any previously described cytokine receptor family. Despite the existence of 12 cysteine residues in the extracellular domain, their relative positions are not characteristic of receptor molecules classified as members of the immunoglobulin superfamily (Williams, A. and Barclay, A.
Annu. Rev. Immunol
. 6:381-405 (1988)), the TNFR family (Smith, C., et al.,
Science
248:1019-1023 (1990)), the hematopoietin receptor family (Cosman, D.
Cytokine
5:95-106 (1993)), or any previously described tyrosine kinase receptors (Hanks, S., et al.,
Science
241:42-52 (1988)).
Thus, there is a need for polypeptides that function as receptor molecules for cytokines and, thereby, function in the transfer of an extracellular signal ultimately to the nucleus of the cell, since disturbances of such regulation may be involved in disorders relating to cellular activation, hemostasis, angiogenesis, tumor metastasis, cellular migration and ovulation, as well as neurogenesis. Therefore, there is a need for identification and characterization of such human polypeptides which can play a role in detecting, preventing, ameliorating or correcting such disorders.
SUMMARY OF THE INVENTION
The present invention provides isolated nucleic acid molecules comprising a polynucleotide encoding at least a portion of the IL17RLP polypeptide having the complete amino acid sequence shown in SEQ ID NO:2 or the complete amino acid sequence encoded by the cDNA clone deposited as plasmid DNA as ATCC Deposit Number 209198 on Aug. 8, 1997. The nucleotide sequence determined by sequencing the deposited IL17RLP clone, which is shown in
FIGS. 1A
,
1
B, and
1
C (SEQ ID NO:1), contains an open reading frame encoding a complete polypeptide of 426 amino acid residues, including an initiation codon encoding an N-terminal methionine at nucleotide positions 10-12, and a predicted molecular weight of about 47.1 kDa. Nucleic acid molecules of the invention include those encoding the complete amino acid sequence excepting the N-terminal methionine shown in SEQ ID NO:2, or the complete amino acid sequence excepting the N-terminal methionine encoded by the cDNA clone in ATCC Deposit Number 209198, which molecules also can encode additional amino acids fused to the N-terminus of the IL17RLP amino acid sequence.
The encoded polypeptide has a predicted leader sequence of 19 amino acids underlined in
FIGS. 1A
,
1
B, and
1
C; and the amino acid sequence of the predicted mature IL17RLP protein is also shown in
FIGS. 1A
,
1
B, and
1
C as amino acid residues 20-426, and as residues 1-407 in SEQ ID NO:2.
Thus, one aspect of the invention provides an isolated nucleic acid molecule comprising a polynucleotide comprising a nucleotide sequence selected from the group consisting of: (a) a nucleotide sequence encoding the IL 17RLP polypeptide having the complete amino acid sequence in SEQ ID NO:2 (i.e., positions −19 to 407 of SEQ ID NO:2); (b) a nucleotide sequence encoding the IL17RLP polypeptide having the complete amino acid sequence in SEQ ID NO:2 excepting the N-terminal methionine (i.e., positions −18 to 407 of SEQ ID NO:2); (c) a nucleotide sequence encoding the predicted mature IL17RLP polypeptide having the amino aci

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