Innate Immune Effector Molecules

Although PAMP-binding to cell surface PRRs is a central mode of cell activation, the activity of effector cells involved in the innate immune response is also influenced by pattern recognition molecules (PRMs).[2] These secreted proteins include mannose-binding proteins (MBP), C-reactive protein (CRP), LPS-binding protein (LBP), and complement. Hepatic synthesis of CRP and LBP is up-regulated during the acute-phase response to infection and is stimulated by LPS, TNF-a, IL-1p, and IL-6.[2,6] CRP recognition of bacterial cell wall lipopolysaccharides leads to the activation of complement, a set of serum proteins with enzymatic activity that are directly bactericidal and promote inflammation. Complement activation results in the generation of products that enhance effector cell recognition and phagocytosis of infectious microorganisms. MBP recognition of bacterial cell surface carbohydrate residues similarly initiates complement activation. Another acute-phase response protein, LBP, is a lipid transfer molecule that facilitates the transfer of bacterial LPS to membrane-bound CD14 found on the surface of macrophages and neutrophils. LPS-CD14 complexes subsequently interact with TLR-4, leading to cell activation. Although CD14 is capable of binding to LPS in an LBP-independent manner, LBP enhances this interaction, and thus greatly enhances host innate detection of LPS present on Gram-negative bacteria.

Innate recognition of PAMPs initiates a series of events that contribute to the development of inflammation through cytokine production and the generation of lipid mediators. The initiation of one event can trigger multiple cascades leading to amplification of the inflammatory response (Fig. 1). For example, LPS activation of the liver-derived protein Factor XII (Hageman Factor) activates both the coagulation and fibrinolytic systems, and products generated by these systems promote a proinflammatory state.[5] Factor XII mediated activation of the kinin system leads to the generation of kalikreins that can feed back to activate Factor XII. Further, activation of Factor XII can lead to the generation of complement products that, in turn, promote the production of leukotrienes. The complex interaction between these pathways culminates in the development of a highly proinflammatory state that enhances host innate immune responses to infectious pathogens.

proteins such as bactericidal-permeability increasing protein (BPI).[2] Both defensins and BPI are directly bactericidal. In addition, defensins can induce cytokine production, whereas BPI is an opsonin that facilitates bacterial clearance.

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