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*
Dompé Research Center, L’Aquila, Italy; and
Pharmakologie, Medizinische Hochschule Hannover, Hannover, Germany
IL-1 signaling is mediated by the type I IL-1R (IL-1RI). The
nonsignaling type II receptor has a regulatory function, since it
reduces IL-1 effects by scavenging free IL-1 molecules. This regulatory
function has been demonstrated only for the soluble form, released from
the membrane receptor by action of specific proteases, but is still
ill-defined for the membrane receptor itself. To assess the function of
membrane IL-1RII, a modified IL-1RII cDNA was constructed, in which the
cleavable domain was replaced with the corresponding uncleavable
sequence of the epidermal growth factor receptor. The human
keratinocyte line HaCaT, which does not express wild-type IL-1RII
(wtIL-1RII), was stably transfected with this modified cDNA
(unconventionally cleavable IL-1RII (uIL-1RII)). Cells transfected with
uIL-1RII expressed the membrane form of IL-1RII, but were unable to
produce the 60-kDa soluble receptor. Upon analysis of IL-1
responsiveness, parental HaCaT and vector-transfected cells (E27),
expressing IL-1RI and the accessory chain IL-1R accessory protein, were
responsive to IL-1. Conversely, cells overexpressing wtIL-1RII (811) or
uIL-1RII (9D4) showed comparable reduction in responsiveness to both
IL-1
(bound by membrane and soluble receptors) and IL-1ß
(recognized by the membrane receptor only), suggesting that the
membrane form of the IL-1RII is mainly responsible for IL-1 inhibition.
In contrast with wtIL-1RII, uIL-1RII did not interact with IL-1R
accessory protein. Thus, the membrane form of IL-1RII possesses strong
IL-1-inhibitory activity, independent of sequestration of the accessory
protein and circumscribed to its ligand sink
function.
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