The role of endogenous interleukin-12 in resistance to murine cytomegalovirus (MCMV) infection and a novel action for endogenous IL-12 p40

Biologically active interleukin-12 (IL-12), comprising a 40 kDa subunit (p4 0) covalently linked to a 35 kDa subunit (p35), is produced in response to a range of infectious stimuli. Here, me demonstrate that mice deficient in either IL-12 p30 (p40(-/-)) or IL-12 p35 (p35(-/-)) are susceptible to muri ne cytomegalovirus (MCMV) infection in terms of survival (Balb/c p35(-/-)) and viral clearance (Balb/c p35(-/-) and Balb/c p30-/-), and this susceptib ility may be correlated to a deficiency in serum interferon-gamma (IFN-gamm a) levels. These data support a role for endogenous IL-12 in controlling MC MV infection. The IL-12 p30 subunit is produced in excess of IL-12 p35, and to date the function of the excess endogenous p40 has been assumed to be o ne of IL-12 antagonism, as demonstrated by experiments with exogenous p40 b oth in vivo and in vitro, We show that Balb/c p35(-/-) alone are significan tly compromised in survival of a sublethal infection and in clearance of vi rus from the spleen. These mice produce a very early IFN-gamma spike (8 h a fter infection) and an aberrant tumor necrosis factor-alpha (TNF-alpha) spi ke (day 2 after infection). MCR IV infection has revealed an altered Balb/c p35(-/-) phenotype compared with Balb/c p40(-/-), and this indicates that endogenous p30 may have an activity independent of and additional to IL-12 antagonism in vivo.