Page 1846 - Williams Hematology ( PDFDrive )

1820 Part XII: Hemostasis and Thrombosis Chapter 111: Megakaryopoiesis and Thrombopoiesis 1821

have reported the presence of plasma and/or an integrin ligand-con- cells in response to inflammatory stimuli. The mature protein is com-
82
taining substratum (e.g., fibronectin or vitronectin) stimulates the pro- posed of 184 amino acids, contains two disulfide bonds, and displays
cess substantially. 64,66 These findings suggest external signals probably both N-linked and O-linked carbohydrate modification. Although IL-6
are required for normal platelet formation. One report suggests the alone fails to affect in vitro megakaryopoiesis, it augments the number
thrombin–antithrombin complex with or without high-density lipo- of megakaryocyte colonies obtained in the presence of IL-3 or stem
83
protein particles mediates the favorable effect of plasma on proplatelet cell factor and exerts primarily a differentiating effect. 84,85 Adminis-
67
formation, although other data suggest prothrombin and its conver- tration of IL-6 to mice or nonhuman primates or patients results in a
sion to thrombin by megakaryocytes inhibit the process. Although the modest thrombocytosis. 86–88 These findings suggest IL-6 contributes to
68
cytokine(s) required for this process is not known, activation of protein megakaryopoiesis in vivo, a conclusion supported by its production by
kinase Cα clearly is necessary for the process to occur. 66 tumor cells in selected cases of paraneoplastic thrombocytosis. How-
89
Platelet formation involves massive reorganization of megakary- ever, genetic elimination of the cytokine fails to significantly affect basal
90
ocyte cytoskeletal components, including actin and tubulin, during platelet production. Evidence suggests the cytokine affects platelet
91
a highly active, motile process in which the termini of the process production indirectly by stimulating thrombopoietin production.
5
branch and issue platelets. The size of the individual platelets formed IL-6 acts through a heterodimeric receptor, composed of a signal-
is of interest. Unfortunately, little is known about this aspect of plate- ing subunit, termed GP130, and an affinity-converting subunit, termed
let formation except that tubulin is proposed to act as a measuring IL-6Rα. GP130 also acts as the signaling subunit for several other
device for the proper site to pinch off platelets from proplatelet pro- cytokines, including IL-11 and leukemia inhibitory factor. Therefore,
cesses. The mechanism of platelet formation clearly must be affected in the finding that these cytokines also stimulate megakaryopoiesis in a
some way by the transcription factor GATA-1, the GPIb-IX complex, manner similar to that of IL-6 is not surprising. IL-11 and leukemia
the Wiskott-Aldrich syndrome protein, and platelet myosin, as defects inhibitory factor act in synergy with IL-3 or stem cell factor to aug-
in each of these genes leads to unusually large or small platelets (Chap. ment megakaryocyte formation. IL-11 is a 23-kDa polypeptide, initially
117). 69,70 Finally, localized cytoplasmic membrane proteolysis, a suble- cloned from a gibbon marrow stromal cell line, whose activity can sup-
thal form of apoptosis, likely plays a role in initiating the final stages of port the proliferation of an IL-6–responsive myeloma cell line. 92,93 Leu-
94
platelet formation. 71 kemia inhibitory factor displays a wide range of activities, including
(1) inducing the acute phase hepatic response, (2) inducing an adren-
EXTRINSIC REGULATION OF ergic-to-cholinergic switch in neurons, (3) inhibiting lipoprotein lipase
in adipocytes, and (4) maintaining pluripotentiality in embryonic cells.
MEGAKARYOCYTE PRODUCTION Like IL-6, IL-11 and leukemia inhibitory factor enhance megakary-
ocytic maturation in vitro 95,96 and augment the effects of IL-3 and stem
HORMONES AND CYTOKINES cell factor on primitive hematopoietic cells. Consistent with the in vitro
Several cytokines, first identified using alternate hematopoietic activ- findings, administration of either recombinant IL-11 or leukemia inhib-
ity assays, affect megakaryocyte development. IL-3, granulocyte-mac- itory factor to rodents, nonhuman primates, or humans produces mod-
rophage colony-stimulating factor, and stem cell factor support the est thrombocytosis. 97–100 Despite the in vitro and in vivo findings, genetic
proliferation of megakaryocytic progenitors in plasma-containing cul- elimination of either leukemia inhibitory factor or the IL-11 receptor
101
tures. 72–74 In 1994, several groups reported the purification and/or clon- has no effect on thrombopoiesis, even when combined with elimina-
ing of thrombopoietin. This cytokine clearly is the primary regulator tion of the thrombopoietin receptor. 102
75
of megakaryopoiesis but cannot explain thrombopoiesis in its entirety.
Stem Cell Factor
Interleukin-3 In contrast to the hematopoietic cytokine family, stem cell factor is
IL-3 is a 25- to 30-kDa protein produced almost exclusively by T more closely related to other hematopoietic proteins that utilize pro-
lymphocytes. The mature human protein contains 133 amino acids, tein tyrosine kinase receptors, such as macrophage colony-stimulating
76
but N-linked carbohydrate modification accounts for the larger than factor and the flt-3 ligand. Nevertheless, stem cell factor stimulates
103
expected Mr of the cytokine. Granulocyte-macrophage colony-stimulat- megakaryocyte colony growth when used in combination with other
ing factor is an 18- to 30-kDa protein also produced by T lymphocytes. cytokines. Moreover, genetic elimination of its receptor c-kit reduces
104
105
However, endothelial cells, monocytes, and fibroblasts also produce megakaryocyte production and the rebound thrombocytosis that
the protein and, like IL-3, granulocyte-macrophage colony-stimulat- occurs following immunosuppressive therapy. 106,107
ing factor is highly modified with both N-linked and O-linked car- Stem cell factor was first identified using several different biologic
bohydrate. Although the two proteins display essentially no primary assays (in addition to this term, the cytokine has been dubbed c-kit
77
108
sequence homology, their tertiary structures are highly related, and ligand, mast cell growth factor, and steel factor). Later studies indi-
78
the receptors for the two cytokines share a common subunit. However, cate the cytokine acts primarily on primitive cells of the hematopoi-
79
the physiologic relevance of IL-3 and granulocyte-macrophage colony- etic, melanogenic, and germ cell lineages. Stem cell factor is a dimeric
stimulating factor for steady-state thrombopoiesis is uncertain. Admin- protein composed of two identical noncovalently linked polypeptides.
istration of the cytokines to mice or humans has only minimal effects The soluble form monomer contains 165 residues, derived by prote-
109
on thrombopoiesis, and genetic elimination of either has no impact olytic cleavage of a membrane-bound splice form of the molecule.
110
on megakaryopoiesis, even when combined with elimination of other The membrane bound form is more active than the soluble cytokine,
thrombopoietic cytokines. 80,81 as intracellular signaling in response to membrane-bound stem cell
111
factor is prolonged in receptor-bearing cells. Moreover, a naturally
Interleukin-6 and Related Cytokines occurring mutant allele of the gene (Sl ), which allows production of
d
IL-6, cloned by several groups using multiple assays (hepatocyte growth, the soluble but not the membrane-bound form of the cytokine, results
112
myeloma cell growth, immunoglobulin secretion, antiviral activity), in a phenotype nearly identical to deletion of the entire locus, again
enhances megakaryocyte maturation. IL-6 is a 26-kDa polypeptide pointing to the importance of the membrane-bound form present on
produced by T lymphocytes, fibroblasts, macrophages, and stromal marrow stromal cells.

Kaushansky_chapter 111_p1813-1828.indd 1821 9/21/15 4:11 PM