A novel cytokine receptor-ligand pair. Identification, molecular characterization, and in vivo immunomodulatory activity.
As part of a large scale effort to discover novel secreted proteins, a cDNA encoding a novel cytokine was identified. Alignments of the sequence of the new protein, designated IL-17B, suggest it to be a homolog of the recently described T cell-derived cytokine, IL-17. By Northern analysis, EST distribution and real-time quantitative polymerase chain reaction analysis, mRNA was detected in many cell types. A novel type I transmembrane protein, identified in an EST data base by homology to IL-17R, was found to bind specifically IL-17B, as determined by surface plasmon resonance analysis, flow cytometry, and co-immunoprecipitation experiments. Readily detectable transcription of IL-17BR was restricted to human kidney, pancreas, liver, brain, and intestines and only a few of the many cell lines tested. By using a rodent ortholog of IL-17BR as a probe, IL-17BR message was found to be drastically up-regulated during intestinal inflammation elicited by indomethacin treatment in rats. In addition, intraperitoneal injection of IL-17B purified from Chinese hamster ovary cells caused marked neutrophil migration in normal mice, in a specific and dose-dependent manner. Together these results suggest that IL-17B may be a novel proinflammatory cytokine acting on a restricted set of target cell types. They also demonstrate the strength of genomic approaches in the unraveling of novel biological pathways.
Shi
Y
Y
Departments of Molecular Biology, Protein Development, Strategic Drug Development, and Cell Biology, Human Genome Sciences, Inc., Rockville, Maryland 20850, USA.
Ullrich
S J
SJ
Zhang
J
J
Connolly
K
K
Grzegorzewski
K J
KJ
Barber
M C
MC
Wang
W
W
Wathen
K
K
Hodge
V
V
Fisher
C L
CL
Olsen
H
H
Ruben
S M
SM
Knyazev
I
I
Cho
Y H
YH
Kao
V
V
Wilkinson
K A
KA
Carrell
J A
JA
Ebner
R
R
D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002465:Cell Movement; D006224:Cricetinae; D018076:DNA, Complementary; D020224:Expressed Sequence Tags; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000166:cytology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D018123:Receptors, Interleukin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053722:Receptors, Interleukin-17; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D000276:Adjuvants, Immunologic; D018076:DNA, Complementary; C109985:IL17RA protein, human; C491673:Il17ra protein, mouse; D020381:Interleukin-17; D008024:Ligands; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D011994:Recombinant Proteins