Annexin I is a local mediator in neural-endocrine feedback control of inflammation.

Abstract

Annexin I is a local mediator in neural-endocrine feedback control of inflammation. J. Neurophysiol. 80: 3120-3126, 1998. Activation of primary afferent nociceptors induces a neural endocrine-mediated inhibition of the inflammatory response via a circuit that includes ascending spinal pathways and activation of the hypothalamic-pituitary adrenal (HPA) axis. This circuit inhibits sympathetic neuron-dependent plasma extravasation (PE) in the rat knee joint produced by bradykinin (BK), but not sympathetic neuron-independent PE produced by platelet activating factor (PAF). Noxious (25 mA) but not non-noxious (2.5 mA) electrical stimulation significantly increased plasma corticosterone concentrations, and intravenous infusion of corticosterone (5 micrograms/min) mimicked inhibition of BK-induced PE produced by noxious stimulation. However, perfusion of corticosterone locally through the knee joint, at doses that do not have a systemic action (i.e., </=1 microM), did not inhibit BK-induced PE. Annexin I (lipocortin-1), a 37-kDa member of a family of phospholipid and calcium binding proteins, can mediate local anti-inflammatory effects of glucocorticoids via a mechanism that is partially dependent on inhibition of phospholipase A2 activity and adhesion and transmigration of polymorphonuclear leukocytes. Because BK-induced PE is dependent on both polymorphonuclear leukocytes and phospholipase A2 activity, we tested the hypothesis that the action of corticosterone to inhibit BK-induced PE is mediated by stimulating the production and release of annexin I. Perfusion of BK (150 nM) through the rat knee joint induces a rapid and sustained increase in PE. Co-perfusion of BK with annexin I (100 ng/ml) through the knee joint mimics the inhibition of BK-induced PE produced by noxious electrical stimulation or by intravenous corticosterone. Co-perfusion of BK with annexin I antibody (LCPS1, 1:60 dilution) prevented the inhibition of BK-induced PE produced by noxious electrical stimulation or intravenous corticosterone adminstration. PAF-induced PE, which is not dependent on polymorphonuclear leukocytes, was not inhibited by local perfusion of annexin I. These data suggest that the inhibitory effect of C-fiber activity on BK-induced PE, acting via an HPA circuit, is mediated by annexin I in the knee joint.