During inflammation and host defense, numerous cellular products are released and cooperate in orchestrating the response of the immune system. Cellular communication is one of these processes that are essential for optimal immunosurveillance. Small protein mediators, termed “chemokines,” have been identified which are released during infection to direct the coordinated trafficking of immune cells. When released within the microenvironmental milieu, a chemokine concentration gradient is established and target cells expressing the cognate chemokine receptor migrate towards the area of highest concentration. Since cells are exposed to multiple chemokines at any given point in time, this gradient is important in allowing target cells to make an executive decision and focus their response.
The chemokine and chemokine receptor nomenclature has evolved from a function-based system, to one which is now based on the number and position of conserved cysteine residues located at the amino terminus. Hence, chemokines and chemokine receptors have been classified into four separate groups: CXC, CC, C, and CX3C. Chemokines can also be grouped into categories based on their level of expression and physiological function. Certain chemokines are constitutively expressed in particular cellular compartments and play crucial roles in organogenesis, cellular development, and differentiation. However, other chemokines are integral mediators of inflammation, are specifically up-regulated during periods of inflammation, promote the infiltration of nonresident immune cells, and participate in the activation of immune cells. Moreover, chemokine receptors are members of the superfamily of GPCRs, similar to ORL1 and the classic opioid receptors.
The chemokines CCL2/monocyte chemoattractant protein (MCP)-l and CCL5/regulated upon activation, normal T cell expressed and secreted (RANTES) are abundantly expressed in numerous disease states and potent chemoattractants of leukocytes. expression of both CCL2/MCP-1 (which binds selectively to CCR2) and CCL5/RANTES (binding CCR1, CCR3, CCR4, and CCR5) is up-regulated by the acute phase of the inflammatory response as well as by other pro-inflammatory stimuli, such as lipopolysaccharide (LPS), phorbol myristate acetate (PMA), and PHA. Although CCL2/MCP-1 attracts a variety of immune cells, it is a strong chemoattractant for monocytes and memory T cells during their infiltration into target tissues. CCL5/RANTES is chemotactic for monocytes and T cells as well, but also dendritic cells, Natural Killer (NK) cells, basophils, eosinophils, and mast cells. Therefore, with the ability to be induced by inflammatory conditions, as well as attract cells of the immune system to sites of inflammation, CCL2/MCP-1 and CCL5/RANTES have been considered to be proinflammatory in nature.