NSAIDs upregulate β₂-integrin expression on human neutrophils through a calcium-dependent pathway

Authors: Fiorucci, S.¹; Santucci, L.¹; Gerli, R.²; Brunori, P. M.¹; Federici, B.¹; Ugolini, B.¹; Fabbri, C.³; Morelli, A.¹

Source: Alimentary Pharmacology & Therapeutics, Volume 11, Number 3, June 1997 , pp. 619-630(12)

Publisher: Wiley-Blackwell

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Abstract:

Background:

Margination of circulating neutrophils (PMN) into the gastric microcirculation is an early and critical event in the pathogenesis of non-steroidal antinflammatory drug (NSAID)-induced gastropathy. This effect is mediated through the upregulation of β₂ integrins on the PMN surface. Aims:

To investigate whether indomethacin modulates: (1) Mac-1 expression; (2) Ca²⁺ mobilization ([Ca²⁺]_i), protein kinase C and nitric oxide accumulation; and (3) mitogen-associated protein kinase phosphorylation in human PMN. Methods:

Human PMN were isolated by centrifugation through a double Ficoll gradient. [Ca²⁺]_i was measured in PMN loaded with fura-2 and Mac-1 expression by flow cytometry. Results:

Indomethacin caused a concentration- and time-dependent upregulation of CD11b and CD18 expression and PMN adhesion to endothelial cells. Maximal upregulation of Mac-1 expression (40-50%) occurred after a 30-min incubation with 0.1 mMindomethacin. The effect was prevented by removing the Ca²⁺. Ionomycin and thapsigargin caused a 7-10-fold increase in [Ca²⁺]_i and a 2-4-fold increase in Mac-1 expression. Indomethacin induced a concentration-dependent phosphorylation of a 41-kDa mitogen-associated protein kinase. Tyrosine kinase inhibitors prevented the effect of indomethacin on Mac-1 expression and Ca²⁺ mobilization. Indomethacin and ionomycin increased superoxide generation, myeloperoxidase secretion and PMN adherence to endothelial cells and stimulated nitric oxide production. Indomethacin-induced Mac-1 upregulation was prevented by a nitric oxide synthase inhibitor. Conclusions:

Indomethacin-induced upregulation of Mac-1 is mediated by changes in [Ca²⁺]_i and nitric oxide. Phosphorylation of the 41-kDa mitogen-associated protein isoform is a previously unreported target of NSAID action. These effects might help to explain the ability of indomethacin to cause gastric neutrophil margination.

Document Type: Research article

DOI: http://dx.doi.org/10.1046/j.1365-2036.1997.00190.x

Affiliations: 1: Sezione di Gastroenterologia ed Endoscopia Digestiva, Dipartimento di Dipartimento di Medicina Clinica, Patologia e Farmacologia, Università degli Studi di Perugia, Perugia, Italy, 2: Istituto di Clinica Medica I e Scienze Oncologiche, Università degli Studi di Perugia, Perugia, Italy 3: Dipartimento di Chirurgia ed Emergenze Chirurgiche, Università degli Studi di Perugia, Perugia, Italy

Publication date: 1997-06-01