Old and new chemokines. Pharmacological regulation of chemokine production and receptor expression: mini-review

Chemokines are a superfamily of proteins that play a crucial role in immune and inflammatory reactions and in viral infections 1,2. Chemokines can be grouped in two main subfamilies defined CXC (or α) and CC (or β) according to the spacing of the first two cysteine residues. Recently, the new chemokines lymphotactin and fractalkine have been reported and define two additional classes of the chemokine superfamily 1,2. CXC chemokines, of which IL-8 is the prototype, are mainly active on neutrophils and T lymphocytes. CC chemokines have a wider spectrum of action, being active on monocytes, granulocytes, T and B lymphocytes, and natural killer (NK) cells 1,2. Lymphotactin, the only C chemokine so far described, is active on T lymphocytes and NK cells. Inflammatory cytokines (e.g. IL-1, tumor necrosis factor (TNF) and IL-6) and bacterial products are potent inducers of chemokine production both in vitro and in vivo. On the contrary, molecules with immunosuppressive and anti-inflammatory activity, such as IL-10 and glucocorticoid hormones, inhibit chemokine production. Chemokines bind to and activate seventransmembrane domain receptors. Five receptors for the CXC chemokines, named CXCR1 to 5, and eight for CC chemokines (CCR1 to 8) have been cloned and characterized in leukocyte populations. Recently, the receptor for fractalkine (CX3CR1) has been cloned while the lymphotactin receptor is still unknown. With only a few exceptions, chemokine receptors bind multiple chemokines and recently it was shown that some of them can function as entry/fusion co-factors for HIV-1 infection 1,2. Emerging evidence indicates that chemokine receptors can be modulated by inflammatory and anti-inflammatory signals. The pattern of expression of chemokine receptors is the major factor that dictates the selectivity of chemokines for different target cells, and regulation of the expression of chemokine receptors may be crucial as a set point for chemokine action. Here, we report the characterization of dendritic cells (DC) as a new important target for chemokine action. In addition, we show that proinflammatory agonists (e.g. LPS) and immunosuppressive and anti-inflammatory cytokines, such as IL-10, are able to selectively modulate the expression of CC chemokine receptors in human mononuclear phagocytes. These results are consistent with a novel paradigm of opposite regulation of chemokines and their receptors by proand anti-inflammatory signals.