Interleukin-one induced inositol phospholipid breakdown in murine macrophages: Possible mechanism of receptor activation

Abstract

Stimulation of mouse peritoneal macrophages by Interleukin-one (IL-1) provoked rapid increases in the levels of inositol mono, bis, tris and tetrakisphosphates (IP₁, IP₂, IP₃ and IP₄ respectively). IP₃ was by far the major metabolite formed and time course studies revealed that IP₂ and IP₃ were formed more rapidly than IP₁ and IP₄ in response to IL-1 stimulation. The IP₂ and IP₃ levels peaked at five seconds while there was a time lag of five seconds in the IP₄ response and the IP₁ levels increased relatively steadily over the time course of the experiments. Levels of IP₂, IP₃ and IP₄ all returned almost to control levels by 60s. The rapid formation of the inositol phosphate metabolites was concomitant with a decrease (84%) in the levels of phosphatidyl-inositol 4,5-bisphosphate (PIP₂) in the macrophages. These results suggest that the mechanism of IL-1 receptor activation is by the rapid hydrolysis of phosphoinositides and generation of the second messenger IP₃.