Open Access

ARTICLE

Unique pattern of expression and inhibition of IL-1 signaling by the IL-1 receptor family member TIR8/SIGIRR

Nadia Polentarutti¹, Giselle Penton Rol^1,2, Marta Muzio^1,3, Daniela Bosisio^1,4, Marco Camnasio^1,5, Federica Riva^1,6, Carla Zoja⁷, Ariela Benigni⁷, Susanna Tomasoni⁷, Annunciata Vecchi¹, Cecilia Garlanda¹, Alberto Mantovani^1,8,9

1 Dept. Immunology and Cell Biology, Mario Negri Institute for Pharmacological Research, Milan, 20157, Italy
2 Current affiliation: Centro de Ingenieria Genetica y Biotecnologia, Havana, Cuba
3 Current affiliation: Dept. Pharmacology, Discovery Research Oncology, Pharmacia Corp., Nerviano, Italy
4 Current affiliation: Inst. for Research in Biomedicine, Bellinzona, Switzerland
5 Current affiliation: MolMed S.p.A. Milan, Italy
6 Current affiliation: Dept. Animal Pathology, Hygiene and Public Health, Faculty of Veterinary Medicine, University of Milan, Milano, Italy
7 Dept. Molecular Medicine, Mario Negri Institute for Pharmacological Research, Bergamo, Italy
8 Centro IDET, Institute of General Pathology, Università degli Studi di Milano, Milan, 20100, Italy N.P. and G.P.R. equally contributed to this project.

* Corresponding Author: Alberto Mantovani,

European Cytokine Network 2003, 14(4), 211-218.

Abstract

TIR8, also known as single Ig IL-1R-related molecule (SIGIRR), is a member of the IL-1 receptor family. The present study was designed to investigate the expression and function of TIR8. TIR8 was mainly expressed in mouse and human epithelial tissues such as kidney, lung and gut. Resting and activated T and B lymphocytes and monocytes-macrophages expressed little or no TIR8, with the exception of the mouse GG2EE macrophage line. In the kidney, the organ with highest mRNA levels, TIR8 expression was confined to epithelial cells and, in situ, to tubular epithelium. A variety of signals failed to regulate TIR8 expression, but LPS reduced TIR8 mRNA transcripts. An NF-κB driven reporter system was used to investigate the function of TIR8. TIR8 did not activate NF-κB expression alone or in concert with IL-1R1. In contrast, TIR8 inhibited signaling from the IL-1R complex. Inhibition required the intracellular portion of TIR8 but the extracellular domain was dispensable for blocking activity. Thus, TIR8 is a unique member of the IL-1R family, with a distinct pattern of epithelial expression, including the kidney and mucosae, and an inhibitory function on IL-1 signaling.

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