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Relaxin Inhibits the Activation of Human Neutrophils: Involvement of the Nitric Oxide Pathway

Departments of Preclinical and Clinical Pharmacology (E.M., A.V., A.N.) and Anatomy, Histology, and Forensic Medicine (S.N., T.B.S., D.B.), Section Histology; University of Florence, I-50139 Florence, Italy

Address all correspondence and requests for reprints to: Prof. Daniele Bani, Dipartimento di Anatomia, Istologia e Medicina Legale, Sezione di Istologia., Viale G. Pieraccini 6, I-50139 Firenze, Italy. E-mail: daniele.bani{at}unifi.it.

In animal models of inflammation, the pregnancy hormone relaxin was shown to reduce the recruitment of leukocytes, especially neutrophils, in inflamed tissues. The current study was designed to clarify whether relaxin could inhibit activation of isolated human neutrophils and, if so, whether the nitric oxide (NO) biosynthetic pathway was involved, as occurs in other relaxin targets. Human neutrophils were preincubated with 1, 10, and 100 nmol/liter porcine relaxin for 1 h before activation with N-formyl-Met-Leu-Phe (10 µmol/liter) or phorbol-12-myristate-13-acetate (0.1 µmol/liter). In selected experiments, the NO synthase inhibitor N^G-monomethyl-L-arginine (L-NMMA, 100 µmol/liter) was added to the samples 30 min before relaxin. In other experiments, chemically inactivated relaxin (10 nmol/liter) was substituted for authentic relaxin. Untreated, nonactivated neutrophils were the controls. Relaxin reduced significantly and in a concentration-dependent fashion the expression of the surface activation marker CD11b, as well as the generation of superoxide anion, the rise of intracellular Ca²⁺, the release of cytoplasmic granules, and the chemotactic migration. These effects of relaxin were blunted by N^G-monomethyl-L-arginine and could not be reproduced by inactivated relaxin. Relaxin also increased neutrophil inducible NO synthase expression and NO generation. This study provides evidence that relaxin inhibits the activation of human neutrophils stimulated by different proinflammatory agents. This novel property of relaxin could be of relevance in toning down maternal neutrophil activation during pregnancy, thereby counteracting the occurrence of pregnancy-related disorders such as preeclampsia, which is regarded as an excess maternal inflammatory response to pregnancy.

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