Volume 14 Supplement 1
Anti-interleukin-6 therapy for treatment of high platelet counts in cGMP-dependent protein kinase I gene-targeted mice
© Zhang et al; licensee BioMed Central Ltd. 2013
Published: 29 August 2013
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 ; however, the role of cGMP/cGKI for platelet biogenesis in vivo is unclear.
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 [2–4]. 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.
We conclude that abnormal signalling of cGMP/cGKI in non-hematopoietic cells affects thrombopoiesis via IL-6 resulting in a reactive thrombocytosis in vivo.
- 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
- 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
- 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
- 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
- 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
- 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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