Chemokine Pharmacology

Although most chemokines recognize more than one receptor, it seems to be a general rule that CC receptors only bind CC chemokines, whereas CXC chemokines are recognized by CXC receptors. Thus there is no crossreactivity between members of the four chemokine subfamilies [8j. However, exceptions to this rule have been published [12-15]. 

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Montana V, Ni Y, Sunjara V, Hua X, Parpura V (2004) Vesicular glutamate transporter-dependent glutamate release from astrocytes. J Neurosci 24 2633-2642 Murphy TH, Blatter LA, Wier WG, Baraban JM (1993) Rapid communication between neurons and astrocytes in primary cortical cultures. J Neurosci 13 2672-2679 Murphy PM, Baggiolini M, Charo IF, Hebert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, Power CA (2000) International union of pharmacology. XXll. Nomenclature for chemokine receptors. Pharmacol Rev 52 145-176... 

Murphy PM, Baggiolini M, Charo IF, et al. International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev 2000 52 145-176. 

Murphy PM. International Union of Pharmacology. Update on chemokine receptor nomenclature. Pharmacol Rev 2002 54 227-229. 

Horuk R. Development and evaluation of pharmacological agents targeting chemokine receptors. Methods 2003 29(4) 369-375. 

The effect of MAPK activation on cellular processes that affect cell function and the resulting pharmacology has been delineated using modem techniques such as knock-out cells and animals [1,3,6]. Activation of MAPK in inflammatory cells such as T-cells, B-cells, macrophages and eosinophils leads to expression and/or activation of pro-inflammatory genes and mediators such as interleukin-1(3 (IL-1(3), TNFa, IL-6, chemokines [e.g., IL-8, macrophage inflammatory factor-1 a, (3 (MIP-la,[3)J, MMPs and toxic molecules such as free radicals and nitric oxide [1,3]. These pro-inflammatory mediators induce cellular proliferation, differentiation, survival, apoptosis and tissue degradation/destruction and help induce chronic inflammation. Inhibition of any one or more of the MAPK family... 

Driscoll KE, Carter JM, Howard BW, Hassenbein DG, Pepelko W, Baggs RB, Oberdorster G (1996) Pulmonary inflammatory, chemokine, and mutagenic responses in rats after subchronic inhalation of carbon black. Toxicology and Applied Pharmacology 136 372-380. 

Cellular responses, as measured by a mixed-lymphocyte reaction, cytotoxic T lymphocyte response, and NK cell activity, were all undiminished, and if anything, there was a slight increase in CTL and NK responses. As would be expected by the histologic profile and the known increases in cytokine and chemokine production associated with the administration of PS ODNs in rodents, in this series of experiments there was no diminution in immune response. Administering a mouse-specific ICAM-1 inhibitor produced reductions in mixed lymphocyte reactions. This inhibition was expected as this is one of the desired pharmacologic effects of reducing ICAM-1 expression. 

Taken together, these results indicate extensive chemotactic interactions betw een the gha cells in MS lesion and the infiltrating cells. Whether these interactions ultimately promote destructive inflammation or recruitment of viral and protective regulatory cells that enhance tissue repair is still not clear. This is a crucial question to answer before potential pharmacological intervention based on chemokines and their receptors could be reinforced for the treatment of the MS. 

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