Differential modulation of endotoxin responsiveness by human caspase—12 polymorphisms.
New research published in Nature indicates that some people carry a single nucleotide polymorphism in the gene encoding caspase-12. This confers hyporesponsiveness to the bacterial cell-wall component lipopolysaccharide (LPS) and subsequently an enhanced susceptibility to bacterial invasion of the bloodstream (septicaemia) and increased mortality.
The polymorphism, which is confined to individuals of African descent, results in the production of a full-length caspase-12 precursor protein (Csp12-L), instead of a truncated caspase-12 protein (Csp12-S). Because other human caspases are involved in two processes — cytokine maturation (which occurs during inflammation through the cleavage of precursors) or apoptosis — Saleh and colleagues examined the whole blood of donors of African origin for apoptotic and inflammatory responsiveness. The presence of Csp12-L correlated with a reduction in LPS-induced cytokine production, whereas both concanavalin-A-stimulated production of most cytokines and apoptotic sensitivity were similar in individuals expressing either variant, indicating that caspase-12 modulates the release of cytokines in response to LPS.
However, although caspase-12 is related to the 'inflammatory' caspases involved in cytokine maturation, neither variant showed any proteolytic activity. The authors suggest that Csp12-L might function as a dominant-negative regulator of the activity of other caspases, potentially by antagonizing the inflammasome (the protein scaffold within which active cytokines are produced) and the associated pro-inflammatory pathways. This is supported by evidence that cell lines transfected with Csp12-L show decreased activation of the main pro-inflammatory transcription factor, nuclear factor-B. Csp12-S was also found to inhibit NF-B activation, although to a lesser extent than Csp12-L.
The polymorphism in caspase-12 is clearly functionally important because preliminary evidence shows that carrying the gene encoding Csp12-L is associated with susceptibility to severe septicaemia and a subsequent increase in mortality. The authors suggest that caspase-12 antagonists might have therapeutic potential for treating septic shock (which results from the overproduction of cytokines in response to LPS) and other inflammatory disorders.
Davina Dadley-Moore
References
Saleh, M. et al. Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature429, 75–79 (2004) | Article | PubMed |
Tracey, K. J. & Warren, H. S. An inflammatory issue. Nature429, 35–36 (2004) | Article | PubMed |
B. Csp12-S was also found to inhibit NF-