Vertebrates, as well as invertebrates and plants, have developed mechanisms to detect and respond to intruders (31, 56). Clearly, inffammation and innate and adaptive immune responses are aimed at destroying the intruders. Gram-negative bacteria contain lipopolysaccharides (LPS) in their outer membranes (82). LPS, which has been studied extensively, is considered the prototypic activator of innate immunity. Picomolar concentrations of LPS are sufficient to stimulate cells of the immune, inffammatory, and vascular systems (81). LPS belongs to the group of molecules produced by pathogens and containing so-called pathogen-associated molecular patterns (PAMPs). PAMPs are recognized by one or more members of a family of transmembrane signaling receptors known as the Toll-like receptor (TLR) family, as well as by intracellular PAMP-detecting molecules, such as nucleotide-binding oligomerization domain 1 (Nod-1), Nod-2, and retinoic acid inducible gene I (RIG-I)(11, 23, 79, 91). To date, 13 different mammalian TLRs have been identified and cloned (77). Activation of TLRs induces intracellular signaling pathways that lead to the production of specific sets of proinffammatory cytokines and chemokines, as well as type I interferons (IFNs) and IFN-inducible gene products (1). IFN was discovered about 50 years ago as a soluble factor that inhibited viral replication upon induction of specific antiviral genes, such as Oas and Mx, in infected cells. The IFNs were initially classified as classical or type I IFNs and immune or type II IFNs. Type I IFNs consist of multiple alpha IFN (IFN-α) proteins, and single IFN-β,-ε,-κ,-ζ (also called limitin), and-ω subtypes, as well as the δ and τ subtypes found in pigs and sheep, respectively (61). IFN-λ1 (interleukin-29 [IL-29]), IFN-λ2 (IL-28A), and IFN-λ3 (IL-28B) function somewhat like type I IFN but belong to a new cytokine family (44). Type II IFN consists of a single gene that codes for the cytokine IFN-γ.

The last few years of research have not only led to a much better characterization of the classical antiviral activities of IFN but have also revealed a number of other biologically important immune regulatory functions of type I IFNs. Together, these results led to the conclusion that type I IFNs are essential links between the early innate responses and the subsequent, more specific adaptive immune responses (7, 38). Type I IFNs induce major histocompatibility complex class I