Chemokines became a focus of attention when it was shown that the envelope glycoprotein of human

immunodeficiency virus (HIV) binds competitively at chemokine receptors.

Together with CD4, these receptors are the port

of entry of HIV-1 into T lymphocytes. Occupation of chemokine receptors, for instance of CXCR-4, prevents the penetration of cells by the HIV-1.47

In some rare individuals, due to a homozygous mutation, the cytokine receptor CCR-5 is

not exposed at the cell surface. The virus cannot gain entry and these fortunate people appear to be immune to infection by HIV.48 The mutation does not appear to induce any deleterious phenotype which indicates that

there is some redundancy among these receptors. Essential functions are well covered in the absence of CCR-5.

Chemokines and activation of integrins on leukocytes

A family of chemokines

Though technically cytokines, the chemokines form a family of small, structurally related proteins (8–14 kDa) originally identified and characterized as chemotactic agents. Leukocytes, when attached to substrate, are capable of sensing concentration differences of chemokines as small as 1% over a distance of 40  m, approximating the linear dimensions of a cell. They respond by moving in the direction of the source, in the process of chemotaxis.46

With respect to transendothelial migration, it is not chemotaxis that directs the movement, because the cells are floating free and buffeted by the blood. In this context, chemokines ‘attract’ leukocytes by stimulating their attachment to and subsequent migration across the endothelial barrier. It is believed that the chemokines, generated by inflamed tissues, are presented on to the surface of the endothelial cell layer. This has been demonstrated for IL-8.49,50 The detection of the chemokines activates adhesion molecules, members of the 1 and 2-integrins on the leukocytes, initiating a series of events that leads to their arrest, flattening and transendothelial migration (see Figure 16.13). By attracting leukocytes to sites of infection/inflammation, chemokines mediate an essential first step in host defence, tissue repair, and healing.

About 40 human chemokines have been identified (Table 16.2). They mainly act on neutrophils, monocytes, lymphocytes, eosinophils, endothelial cells, and their (stem cell) precursors.52,53 The chemokines are small proteins having four conserved cysteines that form two essential intramolecular disulfide bonds (Cys1 with Cys3, and Cys2 with Cys4: Figure 16.7). They are classified

as CC, CXC, and CX3C chemokines, according to the spacing of the first two cysteines in the N-terminal segment. As an exception to the rule, two members of this family only have one cysteine.51

The chemokine receptors are coupled to G proteins

Of the 17 human receptors that have been characterized, most recognize more than one chemokine (Table 16.2). They are linked to both pertussistoxin sensitive (Gi/Go) and insensitive G proteins (G12/G13). It is predominantly the G subunits that carry the signal into cell,55,56 but in the case of the bacterial chemokine, fMLP, activation also occurs through G 12 and G 13.57 The chemokines elicit a number of signal transduction events having different biological effects, which are illustrated in Figure 16.8.58

Activation of integrins

Although the activation of the 1- and 2-integrins can be elicited by overexpression of different PKC isoforms or by phorbol esters59,60 there is the