title: Thrombocytosis as a response to high interleukin-6 levels in cGMP-dependent protein kinase I mutant mice.
abstract: OBJECTIVE
  The purpose of this study was to investigate the influence of cGMP-dependent kinase I (cGKI) on platelet production.
  
  
  RESULTS
  We used hematology analyser to measure platelet counts in conventional cGKI-null mutants (cGKI(L1/L1)), gene-targeted cGKIα/β rescue mice (referred to as cGKI-smooth muscle [SM]) in which cGKI expression is specifically restored only in SM, platelet factor 4-Cre(tg/+); cGKI(L2/L2) mice in which the cGKI protein was specifically deleted in the megakaryocyte/platelet lineage and cGKI-deficient bone marrow-chimeras. Thrombocytosis was detected in cGKI(L1/L1) and in cGKI-SM. In contrast, neither platelet factor 4-Cre(tg/+); cGKI(L2/L2) nor cGKI-deficient bone marrow-chimeras displayed a thrombocytosis phenotype, indicating that the high platelet count in cGKI(L1/L1) and cGKI-SM mutants is attributable to loss of an extrinsic signal rather than reflecting an intrinsic defect in megakaryopoiesis. Cytometric analyses further showed that stimulation of bone marrow-derived wild-type megakaryocytes in vitro using serum preparations obtained from cGKI-SM mutants strongly accelerated megakaryopoiesis, suggesting that the high platelet count develops in response to serum factors. Indeed, using ELISA assay, we found elevated levels of interleukin-6, a known stimulator of thrombopoiesis, in cGKI-SM mutant serum, whereas interleukin-6 levels were unaltered in platelet factor 4-Cre(tg/+); cGKI(L2/L2) mice and cGKI-deficient bone marrow-chimeras. Accordingly, antibody-mediated blockade of interleukin-6 normalized platelet counts in cGKI-SM mice.
  
  
  CONCLUSIONS
  Abnormal cGMP/cGKI signaling in nonhematopoietic cells affects thrombopoiesis via elevated interleukin-6 production and results in thrombocytosis in vivo. Dysfunction of cGMP/cGKI signaling in nonhematopoietic cells contributes to a high platelet count, which is potentially associated with thrombosis.
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Robert
authors.initials: R
authors.lastname: Lukowski
authors.forename: Florian
authors.initials: F
authors.lastname: Gaertner
authors.forename: Michael
authors.initials: M
authors.lastname: Lorenz
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Legate
authors.forename: Katrin
authors.initials: K
authors.lastname: Domes
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Angermeier
authors.forename: Franz
authors.initials: F
authors.lastname: Hofmann
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000235:genetics* / Q000378:metabolism*; D006410:Hematopoiesis / Q000502:physiology; D006487:Hemostasis / Q000502:physiology; D015850:Interleukin-6 / Q000097:blood*; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D010976:Platelet Count; D015398:Signal Transduction / Q000502:physiology; D013922:Thrombocytosis / Q000235:genetics* / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D062965:Cyclic GMP-Dependent Protein Kinase Type I
keywords: cGMP-dependent protein kinase type I; interleukin-6; thrombopoiesis