Increased hypothalamic hydrogen sulphide contributes to endotoxin tolerance by down-modulating PGE 2 production

Whereas some patients have important changes in body core temperature (Tb) during systemic inflammation, others maintain a normal Tb, which is intrinsically associated to immune paralysis. One classical model to study immune paralysis is the use of repeated administration of lipopolysaccharide (LPS), the so-called endotoxin tolerance. However, the neuroimmune mechanisms of endotoxin tolerance remain poorly understood. Hydrogen sulphide (H S) is a gaseous neuromodulator produced in the brain by the enzyme cystathionine β-synthase (CBS). The present study assessed whether endotoxin tolerance is modulated by hypothalamic H S. Rats with central cannulas (drug microinjection) and intraperitoneal datalogger (temperature record) received a low-dose of lipopolysaccharide (LPS; 100 µg kg ) daily for four consecutive days. Hypothalamic CBS expression and H S production rate were assessed, together with febrigenic signalling. Tolerant rats received an inhibitor of H S synthesis (AOA, 100 pmol 1 µL icv) or its vehicle in the last day. Antero-ventral preoptic area of the hypothalamus (AVPO) H S production rate and CBS expression were increased in endotoxin-tolerant rats. Additionally, hypothalamic H S inhibition reversed endotoxin tolerance reestablishing fever, AVPO and plasma PGE levels without altering the absent plasma cytokines surges. Endotoxin tolerance is not simply a reflection of peripheral reduced cytokines release but actually results from a complex set of mechanisms acting at multiple levels. Hypothalamic H S production modulates most of these mechanisms.