Chemokines have been shown to play an important role in leukocyte infiltration into ischemic lesions. Recently, the increased expression of monocyte chemoattractant protein-1 (MCP-1) and cytokine-induced neutrophil chemoattractant (CINC) was observed in experimental stroke models where infiltrated leukocytes were supposed to induce tissue injury, however, the protein level and time course of these chemokines have not been fully elucidated. Therefore, we analyzed the timedependent production of MCP-1 and CINC in the rat brain after transient middle cerebral artery occlusion (MCAO) by means of specific enzymelinked immunosorbent assay systems. The MCP-1 levels in the ipsilateral hemispheres increased from 6 h, peaked at 2 days, and thereafter gradually decreased. The peak MCP-1 concentration was 89.2 ؎ 28.2 ng/g tissue wet weight (mean ؎ SEM, n ‫؍‬ 5, 49.3-fold greater than the contralateral value at the same time, P F 0.05), which is supposed to be high enough to exert its biological effects. In contrast, the maximum CINC concentration that corresponded to 2.9 ؎ 0.7 ng/g tissue wet weight (mean ؎ SEM, n ‫؍‬ 5, 55.0-fold greater than the contralateral value at the same time, P F 0.05), was observed at 6 h. In addition, we confirmed the temporal profile of leukocyte subtypes that infiltrated into the ischemic brain, thus, neutrophil infiltration occurred at early stages (1-3 days), followed by massive infiltration of macrophages at later stages (2-7 days). These studies suggest that MCP-1 in cerebral ischemia actually plays a significant role in the migration of macrophages into the lesion and that the differential temporal production of these chemokines contributes to the regulation of infiltrated leukocyte subtypes. J. Leukoc. Biol. 65: 744-749; 1999.

Infection with Shiga toxin (Stx)-producing Escherichia coli (STEC) causes hemorrhagic colitis and hemolytic uremic syndrome. TMA-15 is a humanized monoclonal antibody against Stx2, a major pathogenic factor. In a mouse infection model that used B2F1, a virulent STEC strain, the efficacy of TMA-15 was assessed when it was administered after bacterial and toxin exposure. In this model, a time-course analysis of the serum Stx2 level showed that the toxin was detectable from 24 h after infection. In an evaluation of the time-dependent efficacy, treatment with TMA-15 up to 24 h after infection ameliorated the lethal challenge, although treatment at 48 h showed no efficacy. To determine the effective dose, escalating doses were administered at 24 h after infection. The number of mice that survived after doses of 0, 0.25, 0.5, 1.0, and 2.0 mg/kg were 0/20, 11/20, 17/20, 20/20, and 20/20, respectively. These findings suggest that TMA-15 shows potential for prevention of severe complications associated with STEC infection.

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We studied the activities of the monocyte chemoattractant proteins MCP-l, MCP-2 and MCP-3 on human embryonic kidney 293-EBNA cells transfected with the MCP-l receptor (CC CKR2B). At 4 nM, MCP-2 induced a Ca H influx which was as potent as that with MCP-l at 4 nM, although the increase by MCP-2 became saturated at higher concentrations. In addition, all three MCPs showed dose-dependent inhibition of adenylyl cyclase activity stimulated by forskolin (ICso values: 0.3 nM for MCP-l, 7 nM for MCP-2, and 1.5 nM for MCP-3).In conclusion, our data indicate that MCP-2 can exert its effects through the MCP-l receptor, CC CKR2B.