IL-1H, AN INTERLEUKIN 1-RELATED PROTEIN THAT BINDS IL-18 RECEPTOR/IL-1Rrp

doi:10.1006/cyto.2000.0799

Cytokine

Volume 13, Issue 1, January 2001, Pages 1-7

https://doi.org/10.1006/cyto.2000.0799 Get rights and content

Abstract

IL-18, or IGIF (interferon-gamma inducing factor), is an IL-1-related, pro-inflammatory cytokine, which plays a pivotal role in systemic and local inflammation. We have identified and characterized IL-1H, a novel IL-1-related molecule. IL-1H appears to be expressed in most tissues with relatively high levels in testis, thymus and uterus. The IL-1H transcripts were stimulated by phorbol ester (PMA) in human cell lines (A431, THP-1 and KG-1) and peripheral blood mononuclear cells (HPBMC) and dendritic cells (NHDC). The protein sequence of IL-1H is mostly related to IL-1ra with a similarity of 36%. A short form of IL-1H was identified, and lacks a 40-amino acid segment in the amino-terminal region of the protein. When expressed in mammalian cells, two secreted polypeptides of IL-1H were identified: an uncleaved and a cleaved form starting with amino acid Val-46. Furthermore, IL-1H binds the IL-18 receptor, but not the IL-1 receptor. These findings suggest that IL-1H may be another ligand for the IL-18 receptor and a new player in the inflammatory and immune responses mediated by the IL-18/IL-18R axis.

References (21)

CA Dinarello
Biological basis for interleukin-1 in disease
Blood
(1996)
SA Greenfeder et al.
Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex
J Biol Chem
(1995)
O Adachi et al.
Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function
Immunity
(1998)
CA Dinarello
Interleukin-18
Methods
(1999)
K Takeda et al.
Defective NK cell activity and Th1 response in IL-18-deficient mice
Immunity
(1998)
K Torigoe et al.
Purification and characterization of the human interleukin-18 receptor
J Biol Chem
(1997)
P Parnet et al.
IL-1Rrp is a novel receptor-like molecule similar to the type I interleukin-1 receptor and its homologues T1/ST2 and IL-1RacP
J Biol Chem
(1996)
D Novick et al.
Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response
Immunity
(1999)
RJ Evans et al.
Mapping receptor binding sites in interleukin (IL)-1 receptor antagonist and IL-1β by site-directed mutagenesis
J Biol Chem
(1995)
WP Arend et al.
Interleukin-1 receptor antagonist: role in biology
Annu Rev Immunol
(1998)

There are more references available in the full text version of this article.

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Citation Excerpt :
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^f1: Correspondence to: Guohua Pan, Department of Endocrinology, Genentech, Inc., M/S-37, 1 DNA Way, South San Francisco, CA 94080 USA. E-mail:[email protected]

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Regular ArticleIL-1H, AN INTERLEUKIN 1-RELATED PROTEIN THAT BINDS IL-18 RECEPTOR/IL-1Rrp

Abstract

Blood

J Biol Chem

Immunity

Methods

Immunity

J Biol Chem

J Biol Chem

Immunity

J Biol Chem

Interleukin-1 receptor antagonist: role in biology

Annu Rev Immunol

Regular Article
IL-1H, AN INTERLEUKIN 1-RELATED PROTEIN THAT BINDS IL-18 RECEPTOR/IL-1Rrp