Thrombocytosis as a Response to High Interleukin-6 Levels in cGMP-Dependent Protein Kinase I Mutant Mice

Abstract

; 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-6production 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. Zhang et al Thrombocytosis in cGKI-Deficient Mice 1821membrane system, and the synthesis of platelet-specific proteins and granules. 11 Together, these changes give rise to the platelet production machinery of mature megakaryocytes that release thrombocytes into the bone marrow (BM)-sinusoid vessels via long cytoplasmic processes, termed proplatelets. 12Fundamental functions of cAMP/cGMP signaling in mature platelets have been recognized for many years [13][14][15] ; however, the role of cAMP or cGMP in the maturation of megakaryocytes and the production of platelets in vivo are much less known. Recent in vitro findings indicate that platelet release from fetal liver cells-derived megakaryocytes is enhanced by high cGMP, but blocked by high cAMP levels in response to prostaglandin I 2 or agonists that directly activate adenylyl cyclase. 16 As in many other cell types, the rate of cGMP production through soluble guanylyl cyclase activity and its degradation via cGMP-hydrolyzing phospodiesterases (PDEs) determine the amplitude, duration, and spatiotemporal distribution of an intraplatelet cGMP signal. 17 Of the 3 known platelet PDE isoforms, 2 isoforms, PDE-2 and PDE-3, may maintain an intensive cross-talk between nitric oxide (NO)/soluble guanylyl cyclase/cGMP and prostaglandin I 2 /adenylyl cyclase/ cAMP because these PDEs limit, with different affinities for their substrates and with different catalytic rates, the levels of both cyclic nucleotides, producing either inactive 5´-AMP or 5´-GMP. 18 Most effects of high intraplatelet cGMP are directly mediated by cGMP-dependent protein kinase type I (cGKI), which is presumably the major effector of NO/cGMP in many cells. 13,14 Interestingly, mature platelets express only the cGKIβ isozyme, whereas in numerous other cell types, such as hippocampal neurons and vascular or visceral smooth muscle (SM) cells, 2 cGKI isoforms, cGKIα and cGKIβ, act downstream of NO and cGMP. 19 In platelets, NO/cGMP signaling via cGKIβ efficiently opposes most agonist-induced and Ca 2+-dependent activation/aggregation steps. 13,20,21 However, the effect of cGKI on megakaryopoiesis and platelet biogenesis in vivo is not completely known.To study the role of cGMP/cGKI signaling in megakaryopoiesis and platelet production in vivo, we took advantage of several established or recently generated transgenic mouse lines. 22Interestingly, we detected high platelet counts in conventional cGKI-null mutants (cGKI L1/L1 ) and in adult cGKI-SM mice with cGKI expression specifically restored in SM, but not in other cell types, 22 whe...

Platelet Turnover in Stable Coronary Artery Disease – Influence of Thrombopoietin and Low-Grade Inflammation

“…In vitro, IL-6 seems to act as a megakaryocyte maturation factor and infusion of IL-6 has been shown to induce modest thrombocytosis [37], [38]. Recently, in vivo experimental studies confirmed the regulatory role of IL-6 in thrombopoiesis [39], [40]. However, in the present study, including stable, high-risk CAD patients, we found no associations between IL-6 and any platelet turnover parameters, although, IL-6 and thrombopoietin were weakly associated.…”

Iron deficiency anemia in cyclic GMP kinase knockout mice

“…3,4 Immunocytochemistry of bone marrow indicated that macrophages but not erythroblasts express cGKI. 1 In contrast, it was found that erythroblasts and erythrocytes purified by immunomagnetic selection using labeled anti-Ter119 MicroBeads followed by magnetic cell sorting are cGKI positive.…”

Expression of cGMP-dependent protein kinase type I in mature white adipocytes

“…Furthermore, hypoadiponectinemia has been associated with elevated levels of inflammatory markers such as C-reactive protein and IL-6 [35,36]. Elevated plasma IL-6 levels that might stem from dysfunctional cGMP/cGKI in fat cells and/or hepatic stellate cells were reported by several studies in the aRM mouse modeI [12,20,22]. This is interesting, because IL-6 may act as a negative regulator of fat cell-derived hormones such as adiponectin and vice versa IL-6 expression can be negatively regulated by adiponectin [37,38].…”

“…However, we want to point out that the presented study shows preliminary data with regard to the mouse models used, because either conventional cGKI À/À or aRM mice were studied. These mice have multiple defects that are not related to the fat cell mass [21,22,30,31,[39][40][41][42]. Therefore, we cannot delineate whether or not the deletion of cGKI in fat cells was the essential cause of the reported disturbance in some fat cell parameters in vivo.…”

“…Moreover, in aRM mice elevated levels of IL-6 [12,20,22] and low levels of the anti-inflammatory factor adiponectin [20] http://dx.doi.org/10.1016/j.bbrc.2014.08.071 0006-291X/Ó 2014 Elsevier Inc. All rights reserved.…”