IL-12 was kindly provided by Stan Wolf (Genetics Institute, Cambridge, Mass.). early development and activation of the innate immune response. Interleukin-12 (IL-12) is a 70-kDa heterodimeric cytokine composed of a 40-kDa heavy chain (p40) and a 35-kDa light chain (p35) (27, 53). IL-12 is produced by monocytes, macrophages, B cells, and dendritic cells primarily in response to bacteria, bacterial products, and intracellular parasites. IL-12 p40, as a monomer or homodimer, is secreted up to a thousandfold excess of the biologically active p70 heterodimer (9). The purpose for the excess secretion of IL-12 p40 is unclear, but recent reports have indicated that p40 homodimers can bind to the IL-12 receptor and inhibit the biological activities of IL-12 in human cells with low efficiency (28) and in mouse cells with much higher efficiency than in human cells (14, 33). IL-12 is a strong inducer of gamma interferon (IFN-) alone or in synergy with other inducers, such as IL-2, phorbol diesters, and anti-CD3 antibodies (7, 27). Other biological activities include enhancement of proliferation (27, 40) and cytotoxicity of activated T and natural killer (NK) cells (27, 43). IL-12 has also been shown to be important in the development of type 1 T helper cells (19, 30, 31). The correlation between IL-12 production or treatment and virus pathogenesis is still poorly understood, and relatively few published studies have addressed the antiviral activity of IL-12. Although the role of IL-12 in viral infections remains to be defined, its immunomodulatory properties may be important in initiating and/or maintaining an antiviral immune response. Based on evidence that IL-12 may be prominently involved in the host response in an infectious disease state, several investigators have begun to explore the role of IL-12 in viral infections. The earliest indication that IL-12 might be involved in virus infections was a study in which IL-12 p40 mRNA NTRK1 expression had been determined in several viral infections in vivo including those by lactate dehydrogenase-elevating virus, mouse hepatitis virus, mouse adenovirus, and lymphocytic choriomeningitis virus (8). Herpes simplex virus (HSV) infection in the cornea was shown to induce IL-12 p40 mRNA expression and p40 protein in the cornea and PF-06873600 draining lymph nodes within 24 h of infection PF-06873600 (26). UV-inactivated virus induced IL-12 p40 mRNA and protein in the cornea, albeit at significantly lower levels than in live virus-infected mice. Culture PF-06873600 of corneal cells from na?ve mice that had been exposed to HSV in vitro did not result in the induction of IL-12 p40 mRNA. Thus, the cellular source of IL-12 is believed to be infiltrating cells, such as Langerhans cells (16), dendritic cells (26), and neutrophils (17), that have undergone an abortive HSV infection. IL-12 is not detectable during lymphocytic choriomeningitis virus infection, and neutralizing IL-12 antibody has no effect on enhanced NK cell-mediated cytotoxicity in this infection (36, 38). In contrast, murine cytomegalovirus transiently induces the production of IL-12, which is responsible PF-06873600 for early NK cell-mediated IFN- production and contributes to viral clearance (35, 37). Administration of recombinant IL-12 (rIL-12) with inactivated pseudorabies virus protects against subsequent lethal challenge with infectious virus, possibly by facilitating the induction of neutralizing immunoglobulin G2a (IgG2a) antibodies (45). This effect of IL-12 is at least in part dependent on IFN-, as the protective effect of IL-12 is largely abrogated in IFN–receptor knockout (IFN- R?/?) mice and administration of IFN- in wild-type mice mimics IL-12 activity. An IFN–dependent mechanism is also responsible for the prophylactic effects of IL-12 in lethal encephalomyocarditis virus infection (39). Mice injected with IL-12 prior to infection with a lethal dose of encephalomyocarditis virus survive. However, IL-12 is unable to provide protection in IFN- R?/? mice. Thus, IL-12 modulates the immune response during pseudorabies and encephalomyocarditis virus infections through the production of IFN-. Recent studies suggest that IL-12 promotes sponsor recovery during a viral respiratory illness (48). BALB/c mice immunized with inactivated respiratory syncytial disease and rIL-12.
