Volume 14 Supplement 1

6th International Conference on cGMP: Generators, Effectors and Therapeutic Implications

Open Access

Anti-interleukin-6 therapy for treatment of high platelet counts in cGMP-dependent protein kinase I gene-targeted mice

  • Lin Zhang1,
  • Robert Lukowski2, 3Email author,
  • Florian Gaertner1,
  • Michael Lorenz1,
  • Kyle R Legate1, 4,
  • Katrin Domes2,
  • Elisabeth Angermeier2,
  • Franz Hofmann2 and
  • Steffen Massberg1, 2
BMC Pharmacology and Toxicology201314(Suppl 1):P80

https://doi.org/10.1186/2050-6511-14-S1-P80

Published: 29 August 2013

Background

The cyclic guanosine-3',5'-monophosphate (cGMP)/cGMP-dependent protein kinase type I (cGKI) pathway is a potent negative regulator of platelet adhesion and aggregation [1]; however, the role of cGMP/cGKI for platelet biogenesis in vivo is unclear.

Results

Here we report thrombocytosis in conventional cGKI null mutants (cGKIL1/L1) and gene-targeted cGKIα/β rescue mice (referred to as cGKI-SM) with cGKI expression specifically restored in smooth muscle (SM), but not in other cell types [24]. In contrast, conditional knockouts lacking the cGKI protein specifically in the megakaryocyte (MK)/platelet lineage (Pf4-Cretg/+; cGKIL2/L2) did not display a related thrombocytosis phenotype, indicating that the high platelet count of cGKIL1/L1 and cGKI-SM mutants is rather a reactive response than an intrinsic defect in megakaryopoiesis. In line with these findings, wild-type (WT) mice engrafted with cGKI-deficient bone-marrow (BM) cells showed full reconstitution of haematopoiesis and normal platelet counts upon myeloablative radiotherapy. Stimulation of BM-derived WT MKs using serum preparations from cGKI-SM mutants strongly accelerated megakaryopoiesis, suggesting that their high platelet counts develop in response to soluble factors. Indeed, we confirm elevated Interleukin-6 (IL-6) serum levels [5, 6], a known cause for reactive thrombocytosis, in cGKI-SM mutants, whereas IL-6 was unaltered in Pf4-Cretg/+; cGKIL2/L2 mice and cGKI-deficient BM chimaeras. Vice versa, antibody-mediated blockage of IL-6 reduced platelet counts in cGKI-SM mice, but not in WT mice.

Conclusion

We conclude that abnormal signalling of cGMP/cGKI in non-hematopoietic cells affects thrombopoiesis via IL-6 resulting in a reactive thrombocytosis in vivo.

Authors’ Affiliations

(1)
Medizinische Klinik und Poliklinik I, Klinikum der Universität, Ludwig-Maximilians-Universität
(2)
Institut für Pharmakologie und Toxikologie, Technische Universität München
(3)
Pharmakologie, Toxikologie und Klinische Pharmazie, Institut für Pharmazie, Universität Tübingen
(4)
Center for NanoScience, Department of Applied Physics, Ludwig-Maximilians-Universität, München

References

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Copyright

© Zhang et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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