Signaling pathway in endotoxin shock identified

Signaling pathway in endotoxin shock identified

Human monocytes exhibit an unconventional one-step pathway of inflammasome activation and IL-1 release in response to lipopolysaccharide (LPS).

Researchers in Nature Communications show that it is mediated by caspases 4 and 5, and characterize caspase 5 cleavage, Syk and calcium signalling as key mediators of this pathway.

Monocytes promote the early host response to infection releasing key pro-inflammatory cytokines, such as IL-1β. The biologically inactive IL-1β precursor is processed to active form by inflammasomes, multi-protein complexes activating caspase-1.

Human monocytes exhibit an unconventional one-step pathway of inflammasome activation in response to lipopolysaccharide (LPS) alone. Although this lineage-restricted mechanism is likely to contribute to the pathology of endotoxin shock, signalling pathways regulating this mechanism are currently unknown.

Researchers report that caspase-4 and caspase-5 mediate IL-1α and IL-1β release from human monocytes after LPS stimulation. Although caspase-4 remains uncleaved, caspase-5 undergoes rapid processing upon LPS treatment.

They also identify an additional caspase-5 cleavage product in LPS-stimulated monocytes, which correlates with IL-1 secretion.

This one-step pathway requires Syk activity and Ca2+ flux instigated by CD14/TLR4-mediated LPS internalization.

Identification of caspase-4/5 as the key determinants of one-step inflammasome activation in human monocytes provides potential targets for therapeutic intervention in endotoxin shock.

http://www.nature.com/ncomms/2015/151028/ncomms9761/full/ncomms9761.html
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