Higher animals have two types of immunity, innate and adaptive. The innate immune system is ancient and the only kind of immune system found in lower phyla. It is responsible for defense against bacterial antigens. Endotoxin, or lipopolysaccharide (LPS), is found in the cell walls of gram negative bacteria such as Escherichia coli. Recognition of LPS by the innate immune system results in an inflammatory response characterized by the production of cytokines such as TNF, IL-1, IL-6, and IL-8; as well as gene activation of ICAM-1 and E-Selectin, among others. The LPS-dependent up-regulation of these genes is due to the up-regulation of kinases which, in turn, up-regulate the NF-kappa B and AP-1 transcription factors. LPS is recognized in the serum by LPS-binding protein (LBP). The LPS-LBP complex is subsequently recognized by CD14. CD14 can exist as a glycophosphatidyl inositol-anchored cell surface protein or a soluble serum protein. Since neither of these forms of CD14 would be competent for cell signaling, a cell surface transmembrane protein may exist to serve as a co-receptor for the CD14/LPS-LBP complex. Another question involves the mechanism by which the cell is able to distinguish host lipid from bacterial lipid.
The C3H/HeJ and C57BL10/ScCr mouse strains both exhibit defects in their ability to respond to LPS. These strains are well-characterized models for LPS-signaling. Research has shown that in both strains, the LPS-defect maps to a single autosomal locus, lps. These lpsd animals display susceptibility to gram-negative bacterial infections, but, interestingly, respond normally to gram-positive bacterial antigens. Genetic mapping has localized lps to a region of chromosome 4.1,2
In Drosophila, the transmembrane receptor, Toll, plays a role in dorsal-ventral embryo polarity. In the adult animal, the Toll receptor plays a role in anti-fungal defenses. The cytoplasmic domain of Toll has homology to the IL-1 RI cytoplasmic domain. Furthermore, the Toll receptor and the IL-1 RI have similar signaling pathways which involve the Drosophila homologs of MyD88, IRAK, I kappa B, and NF-kappa B.8 Mammalian homologs of the Toll receptor have been identified. Human homologs are called the Toll-like receptors, or TLR. A constitutively active TLR4 mutant can induce NF-kappa B activation and expression of IL-1, IL-6, IL-8, and B7-1.3 The gene for TLR4 is located within the lps target area of chromosome 4.1,2 A non-conservative point mutation in Tlr4 in C3H/HeJ mice and null mutation of Tlr4 in C57BL10/ScCr mice have also been identified.1,2
Given the similarity in NF-kappa B signaling, the role of Drosophila Toll in fungal defense, and the findings that the C3H/HeJ and C57BL10/ScCr strains both exhibit defects in TLR4, it seems plausible that TLR4 may represent a co-receptor for CD14. Definitive proof of this hypothesis, however, has not yet been obtained. It will be of interest to see if correction of the defect in the respective mouse strains will restore their ability to respond to LPS. However, the observations that the ability to respond to LPS in these mouse strains can be restored with IFN-gamma treatment and that the animals can respond to high LPS doses, suggest that co-receptors other than TLR4 probably exist.
Likely candidates for CD14 co-receptors may include other human Toll receptor homologs. The Drosophila Toll family and its human homologs are members of the IL-1 receptor family.4 In addition to TLR4, TLR1, TLR2, TLR3, TLR5, and TLR6 have been identified.4,5 Transfection of TLR2 can bestow LPS-responsiveness to a cell line.6,7 How a CD14/TLR complex would distinguish host lipid from bacterial lipid remains to be identified.8,9 Although the end-products of LPS signaling (NF-kappa B activation and up-regulation of TNF, IL-1, IL-6, IL-8, ICAM-1, E-Selectin, and B7-1 among others) are understood, it is still unclear how a LPS-LBP/CD14 complex would interact with a TLR and induce signaling.8