The low-molecular-weight imidazoquinolineamine derivative 1-(2-methyl propyl)-1H-imidazole [4,5-c]quinoline-4-amine (imiquimod) inhibits replication of herpes simplex virus type 2 and cytomegalovirus in infected guinea pigs (6, 24). Imiquimodmediated inhibition of virus replication is related to its ability to induce interferon (IFN). Oral administration of imiquimod induces IFN-␣ in mice, rats, guinea pigs, monkeys, and humans. (New approved nomenclature for IFN genes [9a] is used throughout this paper.) In addition to having antiviral activity, imiquimod was shown to inhibit growth of several transplantable murine tumors, including MC-26 colon carcinoma and Lewis lung carcinoma (71). The induction of IFN-␣ plays a major, but not exclusive, role in this growth inhibition, since an antiserum to mouse IFN-␣ and IFN-␤ significantly reduced the antitumor effect of imiquimod but was not able to abolish it completely.IFN-␣ proteins are represented by a large family of structurally related genes which show about 94% homology at the nucleotide level, while IFN-␤ is encoded by a single gene. IFNA genes are expressed preferentially in cells of lymphoid lineage, and the individual subtypes show cell-type-specific differences in expression (2, 29, 35), while IFNB is expressed in a large variety of cells. The biological significance of the large abundance of IFNA genes is not clear; all IFN-␣ and IFN-␤ subtypes show antiviral and antitumor properties and seem to bind to a common receptor (39); however, some differences between their immunomodulatory effects have been reported (21, 56).Virus-induced expression of IFNA and IFNB genes is mediated by a virus-responsive element (VRE) present in the promoters of IFNA and IFNB genes that, by itself, functions as a virus-specific enhancer and can confer inducibility in infected cells (3,14,19,20,58,65). At least two families of transcriptional factors were shown to play a role in induction of IFN genes that have binding sites within the VRE. One family is the set of IFN-responsive factors IRF-1 and IRF-2, which function as activator and repressor, respectively (22, 23). Overexpression of these two factors can regulate activity of both IFNA and IFNB promoter regions in a transient expression assay; a single nucleotide mutation in the IRF-1 binding site of the murine IFNA4 gene promoter decreased inducibility by about 100-fold (2), and cells expressing IRF-1 antisense mRNA were unable to express IFNB genes (62). However, the role of IRF-1 in induction of the IFN gene has been questioned, since deletion of the IRF-1 gene did not affect virus-mediated inducibility of IFN genes either in mice in vivo or in cultured cells in vitro (53,64). The second family of transcriptional factors are the Bspecific binding proteins that play a role in activation of the IFNB gene (16,19,28,43,77), and recently, a direct role of IFN-induced double-stranded RNA (dsRNA)-dependent kinase in activation of NF-B has been shown (37, 49). Furthermore, it was shown that HMG I(Y) and ATF-2 can bind to the VRE (48...

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Cytokine production has been implicated in the pathogenic mechanisms of infections caused by the staphylococci, since these bacteria may act as strong cytokine inducers. To gain deeper insight into the Th1 immune response activated by these bacteria, we have analyzed the interferon (IFN), interleukin-12 (IL-12) and IL-18-inducing activities of different Staphylococcus aureus (S. aureus), S. epidermidis and S. saprophyticus strains in human monocytes and murine bone marrow macrophages. A large majority of the S. aureus strains elicited the simultaneous production of IL-12 p70 and IFN-alpha in the human monocytes, while the S. epidermidis and S. saprophyticus strains induced only a low level of production, if any, of these cytokines. Furthermore, a majority of the S. aureus strains induced significantly higher IL-12 p70 and IL-18 titers in the murine bone marrow macrophages than did the S. epidermidis and S. saprophyticus strains. As IL-12, IL-18 and IFN-alpha stimulate Th1 differentiation synergistically, we suggest that S. aureus strains bias the immune response toward a Th1 phenotype, whereas S. epidermidis and S. saprophyticus strains provide a weaker stimulus for the production of Th1-inducing cytokines, and accordingly possibly elicit a less extensive Th1-associated adaptive immunity.

The effect of various recombinant cytokines on the induction of interleukin-6 (IL-6) synthesis induced in adherent and nonadherent cells of human peripheral blood mononuclear cells (PBMNC) by bacterial lipopolysaccharide (LPS) or concanavalin A (CA) was studied. The results showed that human interferon-(HuIFN)-alpha, -beta, and gamma at a concentration of 100-10,000 IU/ml enhanced the LPS-induced IL-6 production in the adherent cell fraction of PBMNC. However, in nonadherent cells, treatment with HuIFN-alpha or -beta inhibited the CA-stimulated IL-6 production in a dose-dependent manner. Recombinant (r) IL-2 enhanced the IL-6 production of the adherent cells, while rIL-1 alone in the absence of other inducer induced IL-6 production in the nonadherent cell fraction. Other cytokines such as the recombinant tumor necrosis factor-alpha (rTNF-alpha) or rIL-6 itself did not modulate IL-6 production in human PBMNC. TNF and the interleukins studied did not affect the Sendai virus-induced IFN production in the adherent cells. In contrast, the different IFNs exerted a significant priming effect.