Cytokine‐mediated inflammatory hyperalgesia limited by interleukin‐4

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Abstract
The effect of IL‐4 on responses to intraplantar (i.pl.) carrageenin, bradykinin, TNFα, IL‐1β, IL‐8 and PGE2 was investigated in a model of mechanical hyperalgesia in rats. Also, the cellular source of the IL‐4 was investigated. IL‐4, 30 min before the stimulus, inhibited responses to carrageenin, bradykinin, and TNFα, but not responses to IL‐1β, IL‐8 and PGE2. IL‐4, 2 h before the injection of IL‐1β, did not affect the response to IL‐1β, whereas IL‐4, 12 or 12+2 h before the IL‐1β, inhibited the hyperalgesia (−30%, −74%, respectively). In murine peritoneal macrophages, murine IL‐4 for 2 h before stimulation with LPS, inhibited (−40%) the production of IL‐1β but not PGE2. Murine IL‐4 (for 16 h before stimulation with LPS) inhibited LPS‐stimulated PGE2 but not IL‐1β. Anti‐murine IL‐4 antibodies potentiated responses to carrageenin, bradykinin and TNFα, but not IL‐1β and IL‐8, as well as responses to bradykinin in athymic rats but not in rats depleted of mast cells with compound 40/80. These data suggest that IL‐4 released by mast cells limits inflammatory hyperalgesia. During the early phase of the inflammatory response the mode of action of the IL‐4 appears to be inhibition of the production TNFα, IL‐1β and IL‐8. In the later phase of the response, in addition to inhibiting the production of pro‐inflammatory cytokines, IL‐4 also may inhibit the release of PGs. British Journal of Pharmacology (1999) 126, 45–50; doi:10.1038/sj.bjp.0702266