Sildenafil Can Affect Innate and Adaptive Immune System in Both Experimental Animals and Patients

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Abstract

Sildenafil, a type 5 phosphodiesterase inhibitor (PDE5-I), is primarily used for treating erectile dysfunction. Sildenafil inhibits the degradation of cyclic guanosine monophosphate (cGMP) by competing with cGMP for binding site of PDE5. cGMP is a secondary messenger activating protein kinases and a common regulator of ion channel conductance, glycogenolysis, and cellular apoptosis. PDE5 inhibitors (PDE-Is) found application in cardiology, nephrology, urology, dermatology, oncology, and gynecology. Positive result of sildenafil treatment is closely connected with its immunomodulatory effects. Sildenafil influences angiogenesis, platelet activation, proliferation of regulatory T cells, and production of proinflammatory cytokines and autoantibodies. Sildenafil action in humans and animals appears to be different. Surprisingly, it also acts differently in males and females organisms. Although the immunomodulatory effects of PDE5 inhibitors appear to be promising, none of them reached the point of being tested in clinical trials. Data on the influence of selective PDE5-Is on the human immune system are limited. The main objective of this review is to discuss the immunomodulatory effects of sildenafil in both patients and experimental animals. This is the first review of the current state of knowledge about the effects of sildenafil on the immune system.

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Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents.

Claire Lugnier (2006)

Cyclic nucleotide phosphodiesterases (PDEs), which are ubiquitously distributed in mammalian tissues, play a major role in cell signaling by hydrolyzing cAMP and cGMP. Due to their diversity, which allows specific distribution at cellular and subcellular levels, PDEs can selectively regulate various cellular functions. Their critical role in intracellular signaling has recently designated them as new therapeutic targets for inflammation. The PDE superfamily represents 11 gene families (PDE1 to PDE11). Each family encompasses 1 to 4 distinct genes, to give more than 20 genes in mammals encoding the more than 50 different PDE proteins probably produced in mammalian cells. Although PDE1 to PDE6 were the first well-characterized isoforms because of their predominance in various tissues and cells, their specific contribution to tissue function and their regulation in pathophysiology remain open research fields. This concerns particularly the newly discovered families, PDE7 to PDE11, for which roles are not yet established. In many pathologies, such as inflammation, neurodegeneration, and cancer, alterations in intracellular signaling related to PDE deregulation may explain the difficulties observed in the prevention and treatment of these pathologies. By inhibiting specifically the up-regulated PDE isozyme(s) with newly synthesized potent and isozyme-selective PDE inhibitors, it may be potentially possible to restore normal intracellular signaling selectively, providing therapy with reduced adverse effects.

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Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model.

C. Meyer, A Sevko, M. Ramacher … (2011)

Tumor microenvironment is characterized by chronic inflammation represented by infiltrating leukocytes and soluble mediators, which lead to a local and systemic immunosuppression associated with cancer progression. Here, we used the ret transgenic spontaneous murine melanoma model that mimics human melanoma. Skin tumors and metastatic lymph nodes showed increased levels of inflammatory factors such as IL-1β, GM-CSF, and IFN-γ, which correlated with tumor progression. Moreover, Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs), known to inhibit tumor reactive T cells, were enriched in melanoma lesions and lymphatic organs during tumor progression. MDSC infiltration was associated with a strong TCR ζ-chain down-regulation in all T cells. Coculturing normal splenocytes with tumor-derived MDSC induced a decreased T-cell proliferation and ζ-chain expression, verifying the MDSC immunosuppressive function and suggesting that the tumor inflammatory microenvironment supports MDSC recruitment and immunosuppressive activity. Indeed, upon manipulation of the melanoma microenvironment with the phosphodiesterase-5 inhibitor sildenafil, we observed reduced levels of numerous inflammatory mediators (e.g., IL-1β, IL-6, VEGF, S100A9) in association with decreased MDSC amounts and immunosuppressive function, indicating an antiinflammatory effect of sildenafil. This led to a partial restoration of ζ-chain expression in T cells and to a significantly increased survival of tumor-bearing mice. CD8 T-cell depletion resulted in an abrogation of sildenafil beneficial outcome, suggesting the involvement of MDSC and CD8 T cells in the observed therapeutic effects. Our data imply that inhibition of chronic inflammation in the tumor microenvironment should be applied in conjunction with melanoma immunotherapies to increase their efficacy.

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The regulatory role of nitric oxide in proinflammatory cytokine expression during the induction and resolution of inflammation.

Yoshiro Kobayashi (2010)

Upon inflammation, neutrophils and subsequently monocytes infiltrate into the involved site. Neutrophils perform functions such as bacterial killing or tissue destruction and then undergo apoptosis, whereas monocytes differentiate into macrophages at the site. Macrophages and other phagocytes finally clear apoptotic neutrophils, leading to resolution of the inflammation. One of the key steps during inflammation is leukocyte infiltration, which is controlled chiefly by chemokines for neutrophils and monocytes. The production of these chemokines is regulated positively or negatively by iNOS-derived NO. Although the mechanisms underlying such dual effects of NO remain unknown, the level of NO and duration of NO exposure appear to be determining factors. The clearance of apoptotic neutrophils without causing further proinflammatory responses, on the other hand, is another key event during inflammation. The production of proinflammatory cytokines appears to be actively suppressed by TGF-β and NO, which are produced by phagocytes upon interaction with apoptotic cells. Overall, NO plays a critical role during inflammation and therefore, remains a potential target for developing therapeutics for inflammatory diseases.

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Author and article information

Journal

Journal ID (nlm-ta): J Immunol Res

Journal ID (iso-abbrev): J Immunol Res

Journal ID (publisher-id): JIR

Title: Journal of Immunology Research

Publisher: Hindawi Publishing Corporation

ISSN (Print): 2314-8861

ISSN (Electronic): 2314-7156

Publication date (Print): 2017

Publication date (Electronic): 20 February 2017

Volume: 2017

Electronic Location Identifier: 4541958

Affiliations

Department of Clinical Immunology, Institute of Transplantology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland

Author notes

*Monika Kniotek: mkniotek@ 123456wp.pl

Academic Editor: Eyad Elkord

Author information

Monika Kniotek http://orcid.org/0000-0002-1510-7236

Article

DOI: 10.1155/2017/4541958

PMC ID: 5337856

PubMed ID: 28316997

SO-VID: 459f9f47-a3b7-41f8-8936-ae970e4d6afe

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 17 September 2016

Date revision received : 20 November 2016

Date accepted : 20 December 2016

Funding

Funded by: Narodowe Centrum Nauki

Award ID: 2014/15/D/NZ7/01838

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Sildenafil Can Affect Innate and Adaptive Immune System in Both Experimental Animals and Patients

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Redox Experimental Medicine

Most cited references 63

Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents.

Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model.

The regulatory role of nitric oxide in proinflammatory cytokine expression during the induction and resolution of inflammation.

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