Chemokine(Tego Science, Inc.)

The present data provide the first in vivo evidence that the proinflammatory chemokine, Regulated on Activation Normal T cell Expressed and Secreted (RANTES/CCL5) microinjected directly into the periaqueductal grey in rats, a brain region critical to the processing of pain signals, and a primary site of action of many analgesic compounds, induced hyperalgesia. Pretreatment with antibodies against RANTES/CCL5 prevented the hyperalgesic response, indicating that RANTES/CCL5 is able to interfere with the control of hyperalgesia at the level of the periaqueductal grey and suggesting that chemokine blockers could have analgesic properties.

CCL5/RANTES is a key proinflammatory chemokine produced by virus-infected epithelial cells and present in respiratory secretions of asthmatics. To examine the role of CCL5 in viral lung disease, we measured its production during primary respiratory syncytial virus (RSV) infection and during secondary infection after sensitizing vaccination that induces Th2-mediated eosinophilia. A first peak of CCL5 mRNA and protein production was seen at 18 to 24 h of RSV infection, before significant lymphocyte recruitment occurred. Treatment in vivo with Met-RANTES (a competitive chemokine receptor blocker) throughout primary infection decreased CD4+and CD8+cell recruitment and increased viral replication. In RSV-infected, sensitized mice with eosinophilic disease, CCL5 production was further augmented; Met-RANTES treatment again reduced inflammatory cell recruitment and local cytokine production. A second wave of CCL5 production occurred on day 7, attributable to newly recruited T cells. Paradoxically, mice treated with Met-RANTES during primary infection demonstrated increased cellular infiltration during reinfection. We therefore show that RSV induces CCL5 production in the lung and this causes the recruitment of RSV-specific cells, including those making additional CCL5. If this action is blocked with Met-RANTES, inflammation decreases and viral clearance is delayed. However, the exact effects of chemokine modulation depend critically on time of administration, a factor that may potentially complicate the use of chemokine blockers in inflammatory diseases.