Induction of caspase-11 by inflammatory stimuli in rat astrocytes: lipopolysaccharide induction through p38 mitogen-activated protein kinase pathway

Caspase-11 plays a crucial role in both inflammation and apoptosis. Caspase -11 not only activates caspase-1, that is required for the maturation of pr oinflammatory cytokines such as interleukin (IL)-1 and IL-18, but also acti vates caspase-3, leading to cellular apoptosis under pathological condition s. Here, we cloned the rat homolog of caspase-11, and investigated its indu cibility by inflammatory stimuli and signal transduction pathways involved. Deduced amino acid sequence of rat caspase-11 showed 88.7% similarity to m ouse caspase-11, and in vitro translation of rat caspase-1 I cDNA yielded a pproximately a 43 kDa polypeptide, which was in agreement with predicted pr otein size generated from full-length rat caspase-11 cDNA. The expression o f caspase-11 was strongly induced at both mRNA and protein levels by inflam matory stimuli such as lipopolysaccharide (LPS), interferon-gamma, and tumo r necrosis factor-alpha in C6 rat glial cells as well as primary astrocytes . LPS induced activation of both p38 mitogen-activated protein kinase (MAPK ) and extracellular signal-regulated kinase (ERK) in C6 cells. However, SB2 03580 (specific inhibitor of p38 kinase), but not PD98059 (specific inhibit or of ERK kinase), inhibited LPS induction of caspase-11, indicating that i nduction of caspase-11 by LPS in astrocytes was mediated through the p38 MA PK pathway. Inflammatory induction of caspase-11 in astrocytes may play an important role in both inflammatory responses involving these cells and aut o-regulatory apoptosis of activated astrocytes in inflammatory sites. (C) 2 001 Published by Elsevier Science B.V. on behalf of the Federation of Europ ean Biochemical Societies.