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Sci. STKE, 10 October 2000
Vol. 2000, Issue 53, p. tw3
[DOI: 10.1126/stke.2000.53.tw3]


Immunology Iceberg Sinks Titanic Immune Response!

Regulating the immune response is important business. Excess engagement of inflammatory receptors usually results in toxic consequences for organisms. Thus, inhibitory proteins are required to control the amplitude and duration of such signals. Humke et al. have identified and characterized a protein termed ICEBERG that blocks the proteolytic maturation of interleukin (IL)-1β. In vitro binding assays revealed that the caspase recruitment domain (CARD) located within the prodomain of caspase-1 bound to the CARD domain of ICEBERG. However, RIP2, which is responsible for the oligomerization of caspase-1 (before its cleavage activation) also bound to caspase-1. ICEBERG could preferentially compete with RIP2 for binding with caspase-1, thus blocking caspase-1 oligomerization. Forced expression of ICEBERG blocked the ability of cells to process and secrete mature IL-1β, in the presence of lipopolysaccharide (LPS), a known inducer of IL-1β production. Expression of ICEBERG was increased in cells treated with LPS and by tumore necrosis factor-α (TNF-α), coincident with reduced caspase-1 activity and diminshed release of IL-1β. Also, ICEBERG associated with caspase-1 in an LPS-dependent manner, suggesting that ICEBERG's physiological role is to help attenuate the inflammatory responses mediated by LPS and by TNF-α.

Humke, E.W., Shriver, S.K., Starovasnik, M.A., Fairbrother, W.J., and Dixit, V.M. (2000) ICEBERG: A novel inhibitor of interleukin-1β generation. Cell 103: 99-111. [Online Journal]

Citation: Iceberg Sinks Titanic Immune Response! Sci. STKE 2000, tw3 (2000).

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