Role and regulation of IL-12 in the in vivo response to staphylococcal enterotoxin B

Injection of a staphylococcal superantigen (SAg) such as staphylococcal ent erotoxin B (SEE) in adult mice results in cytokine production and cell prol iferation which can lead to septic shock. The aim of the present work was t o identify the cytokines and co-stimulatory molecules regulating the in viv o systemic release of IFN-gamma, a cytokine known to play an important role in the pathophysiology associated with bacterial infections. We demonstrat e in this study that (i) in contrast to lipopolysaccharide (LPS), SEE admin istration induces high levels of the p70, bioactive form, of IL-12; (ii) IL -12 production in response to SEE requires both CD40-dependent signals and IFN-gamma secretion; (iii) the early systemic release of IFN-gamma (3 h pos t-treatment) in response to SEE is IL-12 independent, while the sustained, late response (6-9 h post-treatment) requires endogenous IL-12 production; (iv) IL-12 produced during the primary SEE response (day 0) is responsible for priming cells in vive to high IFN-gamma production upon secondary chall enge (day 2); (v) the priming effect of IL-12 is TCR unrelated, as SEE-prim ed animals secrete high levels of IFN-gamma in response to both staphylococ cal enterotoxin A and LPS administered 48 h later, The ability of bacterial SAg to induce septic shock and to modulate the immune response to unrelate d antigens may therefore be related to their unique capacity to induce syst emic IL-12 production in vive. These observations also help to explain why SEE-primed animals, known to express an anergic phenotype 48 h post-treatme nt (as judged by defective IL-2 production and proliferation), nevertheless display an increased capacity to secrete the inflammatory cytokine IFN-gam ma.