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Inhibition of phosphodiesterase 9A reduces cytokine-stimulated in vitro adhesion of neutrophils from sickle cell anemia individuals

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Abstract

Objective

Leukocyte adhesion to vessel walls may initiate vaso-occlusion in sickle cell anemia (SCA); however, the extent to which inflammation participates in this mechanism is not understood. This in vitro study investigated whether inflammatory molecules, commonly augmented in SCA, can affect neutrophil adhesive properties and whether cyclic guanosine monophosphate (cGMP)-elevating agents can inhibit such adhesion.

Subjects and methods

Effects of Interleukin 8 (IL-8), tumor necrosis factor-α (TNF-α), granulocyte macrophage-colony stimulating factor (GM-CSF) cytokines, BAY 73-6691 [phosphodiesterase (PDE)-9A-inhibitor], and BAY 41-2271 (guanylate-cylase stimulator) on the adhesive properties of neutrophils from healthy control (CON) and steady-state SCA individuals were determined using static-adhesion assays.

Results

SCA neutrophils demonstrated increased adhesive properties, compared to CON neutrophils; IL-8, TNF-α and GM-CSF increased CON neutrophil adhesion and further increased SCA neutrophil adhesion to fibronectin (FN). The PDE9A inhibitor, BAY-73-6691, significantly reduced basal CON neutrophil and SCA neutrophil adhesion; this was accompanied by decreased SCA neutrophil surface expressions of the L-selectin and CD11b adhesion molecules. BAY-73-6691 also significantly reduced cytokine-stimulated CON neutrophil and SCA neutrophil adhesion to FN; however, this was not accompanied by alterations in adhesion-molecule presentation.

Conclusions

The chronic inflammatory nature of SCA may contribute to leukocyte adhesive functions in SCA. Furthermore, elevation of leukocyte cGMP may be an interesting approach for inhibition of leukocyte adhesion to the vessel wall, even in the presence of inflammatory stimuli.

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Acknowledgments

The authors thank Fernanda Perreira Cunha for assistance with flow cytometry procedures. This study was funded by FAPESP (Fundação de Amparo a Pesquisa do Estado de São Paulo) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), Brazil. The Hematology and Hemotherapy Center, UNICAMP, forms part of the National Institute of Blood, Brazil (INCT de Sangue, CNPq/MCT/FAPESP).

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Authors and Affiliations

  1. Hematology and Hemotherapy Center - Instituto Nacional de Ciência e Tecnologia do Sangue (INCTS), University of Campinas - UNICAMP, Campinas, SP, 13083-970, Brazil

    Lediana Iagalo Miguel, Camila B. Almeida, Fabiola Traina, Andreia A. Canalli, Venina M. Dominical, Sara T. O. Saad, Fernando F. Costa & Nicola Conran

  2. Hemocentro, Rua Carlos Chagas, 480, Cidade Universitária, Barão Geraldo, Campinas, SP, 13083-970, Brazil

    Nicola Conran

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  1. Lediana Iagalo Miguel
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  2. Camila B. Almeida
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  3. Fabiola Traina
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  4. Andreia A. Canalli
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  5. Venina M. Dominical
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  7. Fernando F. Costa
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Correspondence to Nicola Conran.

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Responsible Editor: Graham Wallace.

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Miguel, L.I., Almeida, C.B., Traina, F. et al. Inhibition of phosphodiesterase 9A reduces cytokine-stimulated in vitro adhesion of neutrophils from sickle cell anemia individuals. Inflamm. Res. 60, 633–642 (2011). https://doi.org/10.1007/s00011-011-0315-8

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  • DOI: https://doi.org/10.1007/s00011-011-0315-8

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