Page 222 - Hematology_ Basic Principles and Practice ( PDFDrive )

174 Part II Cellular Basis of Hematology

of such an enzyme modifying effect is that of dipeptidylpeptidase 7. Boulanger MJ, Chow DC, Brevnova EE, et al: Hexameric structure
4 (DPP4). This enzyme has the capability to truncate amongst a and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex.
plethora of growth factors: GM-CSF, G-CSF, IL-3, EPO, and TPO. Science 300:2101–2104, 2003.
The DPP4-truncated GM-CSF manifest less or no activity, yet is 8. Skiniotis G, Boulanger MJ, Garcia KC, et al: Signaling conformations
able to compete by increased receptor-binding capacity to block of the tall cytokine receptor gp130 when in complex with IL-6 and IL-6
the functional activity of the full-length GM-CSF. A similar effect receptor. Nat Struct Mol Biol 12(6):545–551, 2005.
is noted for DPP4-truncated IL-3, and DPP4 truncated-GM-CSF 9. Lupardus PJ, Skiniotis G, Rice AJ, et al: Structural snapshots of full-
and -IL-3 can reciprocally block the stimulating activity of each length Jak1, a transmembrane gp130/IL-6/IL-6Rα cytokine receptor
39
other through common receptor-mediated events. Moreover, the complex, and the receptor-Jak1 holocomplex. Structure 19:45–55, 2011.
full-length and DPP4 truncated-GM-CSF and -IL-3 each trigger 10. Thomas C, Moraga I, Levin D, et al: Structural linkage between
qualitatively, in addition to quantitatively, different intracellular ligand discrimination and receptor activation by type I interferons. Cell
signaling events in terms of proteins, phosphorylated proteins, 146:621–632, 2011.
and microRNAs produced. There is a large and clearly not yet 11. Janes KA, Reinhardt HC, Yaffe MB: Cytokine-induced signaling net-
comprehensive list of biologically active molecules with putative works prioritize dynamic range over signal strength. Cell 135:343–354,
DPP4 truncation sites, 37,38 and the signaling events elicited by 2008.
these truncated molecules should be taken into account in terms 12. Rodig SJ, Meraz MA, White JM, et al: Disruption of the Jak1 gene
of the effects of different cytokines on normal and abnormal cell demonstrates obligatory and nonredundant roles of the Jaks in cytokine-
growth. induced biologic responses. Cell 93:373–383, 1998.
To add another layer of complexity to the emerging knowledge of 13. Neubauer H, Cumano A, Müller M, et al: Jak2 deficiency defines an
cytokine induced receptor-mediated intracellular signaling is the state essential developmental checkpoint in definitive hematopoiesis. Cell
of the cell itself. It is now becoming clear that once a cell is removed 93:397–409, 1998.
from its in vivo hypoxic environment to that of ambient air, which 14. Parganas E, Wang D, Stravopodis D, et al: Jak2 is essential for sig-
is defined here as normoxic (~21% O 2 ), a phenomenon termed ext- naling through a variety of cytokine receptors. Cell 93:385–395,
raphysiologic oxygen shock/stress (EPHOSS) is initiated and changes 1998.
the metabolism of hematopoietic stem and progenitor cells, and likely 15. Nosaka T, Van Deursen JM, Tripp RA, et al: Defective lymphoid devel-
other cell types through an axis encompassing the mitochondrial opment in mice lacking Jak3. Science 270:800–802, 1995.
permeability transition pore-cyclophilin D-p53, which also involves 16. Thomis DC, Gurniak CB, Tivol E, et al: Defects in B lymphocyte
hypoxia inducing factor-1α and the hypoxamir microRNA 210. 40,41 maturation and T lymphocyte activation in mice lacking Jak3. Science
Thus the intracellular signaling that one detects by assessing the 270:794–797, 1995.
effects of a cytokine on a cell collected and processed under ambient- 17. Velazquez L, Fellous M, Stark GR, et al: A protein tyrosine kinase in the
air (normoxia) may not exactly mimic how that cytokine might signal interferon alpha/beta signaling pathway. Cell 70:313–322, 1992.
in a cell in its in vivo hypoxic environment. Those differences in 18. O’Shea JJ, Gadina M, Schreiber RD: Cytokine signaling in 2002:
cascades in signaling molecules may manifest differently under physi- new surprises in the Jak/Stat pathway. Cell 109(Suppl):S121–S131,
ologic and pathologic conditions. Ambient air induced EPHOSS, as 2002.
compared with the in vivo hypoxic environment, results in differ- 19. Reich NC: STAT dynamics. Cytokine Growth Factor Rev 18:511–518,
ences in hematopoietic stem and progenitor numbers and activity. 2007.
Cyclophilin D-/- and p53-/- have EPHOSS protective effects, while 20. Meraz MA, White JM, Sheehan KC, et al: Targeted disruption of the
hypoxia inducing factor 1α-/- and microRNA 210-/- abrogate the Stat1 gene in mice reveals unexpected physiologic specificity in the
protective effects achieved by the harvesting and processing cells JAK-STAT signaling pathway. Cell 84:431–442, 1996.
under hypoxic conditions. 40 21. van de Veerdonk FL, Plantinga TS, Hoischen A, et al: STAT1 mutations
How cytokine-receptor signaling is influenced by enzyme trun- in autosomal dominant chronic mucocutaneous candidiasis. N Engl J
cated cytokines/growth factors, such as seen with DPP4 truncated Med 365:54–61, 2011.
proteins, 37–39 and consideration of the in vivo hypoxic condition cells 22. Park C, Li S, Cha E, et al: Immune response in Stat2 knockout mice.
are usually bathed in will have to be assessed for more detailed and Immunity 13:795–804, 2000.
potentially greater physiologic and pathologic understanding of 23. Akira S: Roles of STAT3 defined by tissue-specific gene targeting.
intracellular signaling and its modification for clinical advantage. 40,41 Oncogene 19:2607–2611, 2000.
Also, how multiple cytokines signal together under these conditions 24. Mantel C, Messina-Graham S, Moh A, et al: Mouse hematopoietic cell-
and with that of synthesized small molecules currently being used for targeted STAT3 deletion: stem/progenitor cell defects, mitochondrial
ex vivo expansion of hematopoietic stem cells should be consid- dysfunction, ROS overproduction, and a rapid aging-like phenotype.
ered. 42,43 It may be that such evaluations will be critical for the Blood 120:2589–2599, 2012.
development of more efficacious treatments for cancer and related 25. Wurster AL, Tanaka T, Grusby MJ: The biology of Stat4 and Stat6.
hematologic disorders. Oncogene 19:2577–2584, 2000.
26. Remmers EF, Plenge RM, Lee AT, et al: STAT4 and the risk of rheumatoid
arthritis and systemic lupus erythematosus. N Engl J Med 357:977–986,
REFERENCES 2007.
27. Masuda A, Matsuguchi T, Yamaki K, et al: Interleukin-15 induces rapid
1. Boulay J, O’Shea J, Paul W: Molecular phylogeny within type I cytokines tyrosine phosphorylation of STAT6 and the expression of interleukin-4
and their cognate receptors. Immunity 19:159–163, 2003. in mouse mast cells. J Biol Chem 275(38):29331–29337, 2000.
2. Bazan J: Structural design and molecular evolution of a cytokine receptor 28. Broxmeyer HE, Bruns H, Zhang S, et al: Th1 cells regulate hema-
superfamily. Proc Natl Acad Sci USA 87:6934–6938, 1990. topoietic progenitor cell homeostasis by production of oncostatin M.
3. Boulay JL, Paul WE: The interleukin-4 family of lymphokines. Curr Immunity 16:815–825, 2002.
Opin Immunol 4:294–298, 1992. 29. Liu X, Robinson GW, Wagner KU, et al: Stat5a is mandatory for adult
4. Horan T, Wen J, Narhi L, et al: Dimerization of the extracellular domain mammary gland development and lactogenesis. Genes Dev 11(2):179–
of granuloycte-colony stimulating factor receptor by ligand binding: a 186, 1997.
monovalent ligand induces 2:2 complexes. Biochemistry 35:4886–4896, 30. Udy GB, Towers RP, Snell RG, et al: Requirement of STAT5b for sexual
1996. dimorphism of body growth rates and liver gene expression. Proc Natl
5. Ghoreschi K, Laurence A, O’Shea J: Janus kinases in immune cell signal- Acad Sci USA 94(14):7239–7244, 1997.
ing. Immunol Rev 228:273–287, 2009. 31. Teglund S, McKay C, Schuetz E, et al: Stat5a and Stat5b proteins have
6. McKinstry WJ, Li CL, Rasko JE, et al: Cytokine receptor expression on essential and nonessential, or redundant, roles in cytokine responses. Cell
hematopoietic stem and progenitor cells. Blood 89:65–71, 1997. 93(5):841–850, 1998.