Editors' ChoiceImmunology

New Function for Histamine

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Science's STKE  17 Jun 2003:
Vol. 2003, Issue 187, pp. tw228-TW228
DOI: 10.1126/stke.2003.187.tw228

During an allergic reaction to a specific antigen, histamine that is released by mast cells and basophils acts on vascular endothelial cells (ECs) as part of the inflammatory response. As a consequence, the vasculature becomes increasingly more leaky, allowing leukocyte infiltration into tissues. Histamine also stimulates ECs to synthesize vasodilators. Furthermore, mast cells release tumor necrosis factor (TNF) at sites of allergic inflammation, a potent stimulator of leukocyte recruitment. Wang et al. propose that as the allergic reaction evolves, histamine may actually limit TNF action by both reducing the availability of TNF receptors on endothelial cells and neutralizing soluble TNF. Treatment of cultured human ECs with histamine caused TNF receptors to be shed from the cell surface. This seemed to occur through the action of a metalloproteinase called TNF-α-converting enzyme (TACE), because a TACE inhibitor blocked this effect. Histamine treatment also mobilized a large reserve of TNF receptor in the Golgi complex to the plasma membrane, where the receptors were subsequently shed. Activation of TACE by histamine apparently involved the ERK1 and 2 mitogen-activated protein kinase (MAPK) pathway, as determined by a screen of various pharmacological inhibitors. Treatment of cells with histamine before exposure to TNF diminished TNF-induced activation of the NF-κB signaling pathway, which regulates the expression of proinflammatory genes. The authors conclude that, in addition to its more well known proinflammatory action, histamine may have an anti-inflammatory effect by desensitizing the EC response to TNF.

J. Wang. R. S. Al-Lamki, H. Zhang, N. Kirkiles-Smith, M. L. Gaeta, S. Thiru, J. S. Pober, J. R. Bradley, Histamine antagonizes tumor necrosis factor (TNF) signaling by stimulating TNF receptor shedding from the cell surface and Golgi storage pool. J. Biol. Chem. 278, 21751-21760 (2003) [Abstract] [Full Text]

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