Chemotaxis

To enter the inflamed tissues, adherent leukocytes have to cross the vascular endothelial lining and migrate along increasing concentrations of biochemical signals emanating from the site of injury. This locomotion (chemotaxis) may be initiated, augmented or directed by a variety of chemotactic stimuli such as humoral components (C5a) and coagulation products (thrombin), and those which are released by microorganisms (fMLP), platelets and other sources. Early events in inflammation trigger platelet aggregation and the release of platelet-activating factor (PAF), platelet-derived growth factor (PDGF), platelet factor 4 (PF4) and transforming growth factor (3 (TGF0) (Figure 1), all of which are potent inducers of leukocyte mobilization. Neutrophils, the first leukocytes to arrive at the site, contrib ute to complement activation (C5a), and also release chemoattractants (chemokines, PAF, TGF(3), thereby-amplifying inflammation and promoting monocyte accumulation. Monocytes, in turn, influence subsequent events by generating numerous plciotropic products (1L-1, TNFot, chemokines, PAF, TGFpJ) which promote leukocyte-endothelial cell adhesion and recruit additional cells (Figure 1). These leukocyte-derived products have an enormous cascading impact on the evolution of an inflammatory or immune response.

Among these amplification products is the super-family of nearly 30 chemotactic proteins, the chemokines (Figures 1 and 3). These small (8-10 kDa) proteins contain four cysteine residues in highly conserved positions, and have been subdivided structurally into two families based on the arrangement of the first two cysteines which are adjacent in (3 chemokines (C-C), but interrupted by a single amino acid in the a chemokines (C-X-C). Most a chemokines preferentially elicit and activate neutrophils to destroy foreign agents, while (3 chemokines mobilize mononuclear cells, enabling a progression of cell recruitment into an inflammatory site. Secreted by a wide variety of myeloid and non-myeloid cells including neutrophils, monocytes, endothelial cells, fibroblasts, and some tumor cells in response to a Chemokines

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Figure 3 Chemokines and their receptors. Chemokines are represented by two subfamilies based on the arrangement of their first two cysteines, which are adjacent (C-C) in p chemokines and separated by a single amino acid (C-X-C) in a chemokines. Polymorphonuclear neutrophils (PMNs) express type A and B receptors for a chemokines, and mononuclear leukocytes (MNLs) express different combinations of the five (3 chemokine receptors which have been identified to date.

Table 1 Consequences of gene targeting (knockout) of adhesion molecules

Null mutation

Phenotype of homozygotes

Selectin family

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