TREATMENT WITH HOMODIMERIC INTERLEUKIN-12 (IL-12) P40 PROTECTS MICE FROM IL-12-DEPENDENT SHOCK BUT NOT FROM TUMOR-NECROSIS-FACTOR ALPHA-DEPENDENT SHOCK

The role of interleukin-12 (IL-12) was investigated in different shock models using anti-IL-12 reagents. IL-12 is composed of two disulfide- bonded subunits, p35 and p40. The IL-12 p40 homodimer (p40)(2) has bee n shown to be a potent IL-12 antagonist in vitro. We investigated its in vivo inhibitory capacity in different shock models of mice. We coul d demonstrate that (p40)(2) is able to protect mice from septic shock in primarily IL-12-dependent models such as the Shwartzman reaction an d lipopolysaccharide (LPS)-induced shock, whereas (p40)(2) has no effe ct in the tumor necrosis factor alpha-dependent LPS/D-GaIN shock model . In IL-12-dependent shock models, (p40)(2) inhibits IL-12-induced gam ma interferon production and thereby interferes with the cascade of cy tokine release, finally leading to death.