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

  • 1,
  • 2, 3Email author,
  • 1,
  • 1,
  • 1, 4,
  • 2,
  • 2,
  • 2 and
  • 1, 2
BMC Pharmacology and Toxicology201314 (Suppl 1) :P80

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

  • Published:

Keywords

  • Platelet Adhesion
  • Thrombocytosis
  • Conditional Knockout
  • Normal Platelet Count
  • High Platelet Count

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, München, Germany
(2)
Institut für Pharmakologie und Toxikologie, Technische Universität München, Forschergruppe 923, München, Germany
(3)
Pharmakologie, Toxikologie und Klinische Pharmazie, Institut für Pharmazie, Universität Tübingen, Tübingen, Germany
(4)
Center for NanoScience, Department of Applied Physics, Ludwig-Maximilians-Universität, München, München, Germany

References

  1. Massberg S, Sausbier M, Klatt P, Bauer M, Pfeifer A, Siess W, Fassler R, Ruth P, Krombach F, Hofmann F: Increased adhesion and aggregation of platelets lacking cyclic guanosine 3',5'-monophosphate kinase I. J Expt Med. 1999, 189: 1255-1264. 10.1084/jem.189.8.1255.View ArticleGoogle Scholar
  2. Weber S, Bernhard D, Lukowski R, Weinmeister P, Worner R, Wegener JW, Valtcheva N, Feil S, Schlossmann J, Hofmann F, Feil R: Rescue of cGMP kinase I knockout mice by smooth muscle specific expression of either isozyme. Circ Res. 2007, 101: 1096-1103. 10.1161/CIRCRESAHA.107.154351.View ArticlePubMedGoogle Scholar
  3. Lukowski R, Rybalkin SD, Loga F, Leiss V, Beavo JA, Hofmann F: Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes. Proc Natl Acadf Sci USA. 2010, 107: 5646-5651. 10.1073/pnas.1001360107.View ArticleGoogle Scholar
  4. Leiss V, Friebe A, Welling A, Hofmann F, Lukowski R: Cyclic GMP kinase I modulates glucagon release from pancreatic alpha-cells. Diabetes. 2011, 60: 148-156. 10.2337/db10-0595.PubMed CentralView ArticlePubMedGoogle Scholar
  5. Lut SZZ, Hennige AM, Feil S, Peter A, Gerling A, Machann J, Krober SM, Rath M, Schurmann A, Weigert C, Haring HU, Feil R: Genetic ablation of cGMP-dependent protein kinase type I causes liver inflammation and fasting hyperglycemia. Diabetes. 2011, 60: 1566-1576. 10.2337/db10-0760.View ArticleGoogle Scholar
  6. Mitschke MM, Hoffmann LS, Gnad T, Scholz D, Kruithoff K, Mayer P, Haas B, Sassmann A, Pfeifer A, Kilic A: Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB J. 2013, 27: 1621-1630. 10.1096/fj.12-221580.View ArticlePubMedGoogle Scholar

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