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Abstract

Neopterin is produced by monocytes and is a useful biomarker of inflammatory activation. We found that neopterin enhanced in vivo and in vitro granulopoiesis triggered by the stromal-cell production of cytokines in mice. The effects of neopterin on B lymphopoiesis during the enhancement of granulopoiesis were determined using the mouse model of senescent stromal-cell impairment (SCI), a subline of senescence-accelerated mice (SAM). In non-SCI mice (a less senescent stage of SCI mice), treatment with neopterin decreased the number of colonies, on a semisolid medium, of colony-forming units of pre–B-cell progenitors (CFU-preB) from unfractionated bone marrow (BM) cells, but not that from a population rich in pro-B and pre-B cells without stromal cells. Neopterin upregulated the expression of genes for the negative regulators of B lymphopoiesis such as tumor necrosis factor-α (TNF-α ), interleukin-6 (IL-6), and transforming growth factor-β (TGF-β) in cultured stromal cells, implying that neopterin suppressed the CFU-preB colony formation by inducing negative regulators from stromal cells. The intraperitoneal injection of neopterin into non-SCI mice resulted in a marked decrease in the number of femoral CFU-preB within 1 day, along with increases in TNF-α and IL-6 expression levels. However, in SCI mice, in vivo and in vitro responses to B lymphopoiesis and the upregulation of cytokines after neopterin treatment were less marked than those in non-SCI mice. These results suggest that neopterin predominantly suppressed lymphopoiesis by inducing the production of negative regulators of B lymphopoiesis by stromal cells, resulting in the selective suppression of in vivo B lymphopoiesis. These results also suggest that neopterin facilitated granulopoiesis in BM by suppressing B lymphopoiesis, thereby contributing to the potentiation of the inflammatory process; interestingly, such neopterin function became impaired during senescence because of attenuated stromal-cell function, resulting in the downmodulation of the host-defense mechanism in the aged.

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References

Rembold H, Gyure WL. Biochemistry of the pteridines. Angew Chem Int Ed Engl 11:1061–1072, 1972.

Huber C, Batchelor JR, Fuchs D, Hausen A, Lang A, Niederwieser D, Reibnegger G, Swetly P, Troppmair J, Wachter N. Immune response-associated production of neopterin. Release from macrophages primarily under control of interferon-gamma. J Exp Med 160:310–316, 1984.

Niederwieser D, Huber C, Gratwohl A, Bannert P, Fuchs D, Hausen A, Reinbnegger G, Speck B, Wachter H. Neopterin as a new biochemical marker in the clinical monitoring of bone marrow transplant recipients. Transplantation 38:497–500, 1984.

Reibnegger G, Aulitzky W, Huber C, Margreoter R, Riccabona G, Wachter H. Neopterin in urine and serum of renal allograft recipients. J Clin Chem Biochem 24:770–775, 1986.

Schobersberger W, Hoffmann G, Hobisch-Hagen P, Bock G, Volkl H, Baier-Bitterlich G, Wirleitner B, Wachter H, Fuchs D. Neopterin and 7,8-dihydroneopterin induce apoptosis in the rat alveolar epithelial cell line L2. FEBS Lett 397:263–268, 1996.

Kojima S, Nomura T, Icho T, Kajiwara Y, Kitabatake K, Kubota K. Inhibitory effect of neopterin on NADPH-dependent superoxide-generating oxidase of rat peritoneal macrophages. FEBS Lett 329: 125–128, 1993.

Schobersberger W, Jelkmann W, Fandrey J, Frede S, Wachter H, Fuchs D. Neopterin-induced suppression of erythropoietin production in vitro. Pteridines 6:12–16, 1995.

Uberall F, Werner-Felmayer G, Schubert C, Grunicke HH, Wachter H, Fuchs D. Neopterin derivatives together with cyclic guanosine monophosphate induce c-fos gene expression. FEBS Lett 352:11–14, 1994.

Schobersberger W, Hoffmann G, Grote J, Wachter H, Fuchs D. Induction of inducible nitric oxide synthase expression by neopterin in vascular smooth muscle cells. FEBS Lett 377:461–464, 1995.

10.

Kibourn RG, Traber DL, Szabo C. Nitric oxide and shock. Dis Mon 43: 277–348, 1997.

11.

Aizawa S, Hiramoto M, Araki S, Negishi S, Kimura Y, Hoshi G, Kojima S, Wakasugi K. Stimulatory effects of neopterin on hematopoiesis in vitro are mediated by activation of stromal-cell function. Hematol Oncol 16:57–67, 1998.

12.

Aizawa S, Hamamoto H, Araki S, Hoshi H, Kojima S, Wakasugi K. In vivo stimulatory effects of neopterin on hematopoiesis. Pteridines 9:13–17, 1998.

13.

Takeda T, Hosokawa M, Takeshita S, Irino M, Higuchi K, Matsushita T, Tomita Y, Yasuhira K, Hamamoto H, Shimizu K, Ishii M, Yamamuro T. A new murine model of accelerated senescence. Mech Ageing Dev 17:183–194, 1981.

14.

Izumi-Hisha H, Ito Y, Sugimoto K, Oshima H, Mori KJ. Age-related decrease in the number of hemopoietic stem cells and progenitors in senescence accelerated mice. Mech Ageing Dev 56:89–97, 1990.

15.

Tsuboi I, Morimoto K, Horie T, Mori KJ. Age-related changes in various hemopoietic progenitor cells in senescence-accelerated (SAMP) mice. Exp Hematol 19:874–877, 1991.

16.

Tsuboi I, Morimoto K, Hirabayashi Y, Li GX, Aizawa S, Mori KJ, Kanno J, Inoue T. Senescent B lymphopoiesis is balanced in suppressive homeostasis: decrease in interleukin-7 and transforming growth factor-β levels in stromal-cells of senescence-accelerated mice. Exp Biol Med (Maywood) 229:494–502, 2004.

17.

Riley RL, Kruger MG, Elia J. B cell precursors are decreased in senescent BALB/c mice, but retain normal mitotic activity in vivo and in vitro. Clin Immunol Immunopathol 59:301–313, 1991.

18.

Fuchs D, Stahl-Hennig C, Gruber A, Murr C, Hunsmann G, Wachter H. Neopterin—its clinical use in urinalysis. Kidney Int Suppl 47:S8–S11, 1994.

19.

Nagaoka H, Gonzalez-Aseguinolaza G, Tsuji M, Nussenzweig MC. Immunization and infection change the number of recombination activating gene (RAG)-expressing B cells in the periphery by altering immature lymphocyte production. J Exp Med 191:2113–2120, 2000.

20.

Ueda Y, Yang K, Foster SJ, Kondo M, Kelsoe G. Inflammation controls B lymphopoiesis by regulating chemokine CXCL12 expression. J Exp Med 199:47–58, 2004.

21.

Ueda Y, Kondo M, Kelsoe G. Inflammation and the reciprocal production of granulocytes and lymphocytes in bone marrow. J Exp Med 201:1771–1780, 2005.

22.

Wirleitner B, Obermoser G, Bock G, Neurauter G, Schennach H, Sepp N, Fuchs D. Induction of apoptosis in human blood T cells by 7,8-dihydroneopterin: the difference between healthy controls and patients with systemic lupus erythematosus. Clin Immunol 107:152–159, 2003.

23.

Nemunaitis J, Tompkins CK, Andrews DF, Singer JW. Transforming growth factor beta expression in human marrow stromal-cells. Eur J Haematol 46:140–145, 1991.

24.

Hoffman G, Schobersberger W, Frede S, Pelzer L, Fandrey J, Wachter H, Fuchs D, Grote J. Neopterin activates transcription factor nuclear factor-κB in vascular smooth muscle cells FEBS Lett 391:181–184, 1996.

25.

Hoffman G, Kenn S, Wirleitner B, Deetjen C, Trede S, Smolny M, Rieder J, Fuchs D, Baier-Bitterlich G, Schobersberger W. Neopterin induces nitric oxide-dependent apoptosis in rat vascular smooth muscle cells. Immunobiol 199:63–73, 1998.

26.

Lee G, Namen AE, Gillis S, Ellingsworth LR, Kincade PW. Normal B cell precursors responsive to recombinant murine IL-7 and inhibition of IL-7 activity by transforming growth factor-beta. J Immunol 142:3875–3883, 1989.

27.

Fernandez S, Knopf MA, Shankar G, McGillis JP. Calcitonin gene-related peptide indirectly inhibits IL-7 responses in pre-B cells by induction of IL-6 and TNF-alpha in bone marrow. Cell Immunol 226: 67–77, 2003.

28.

Barak M, Gruener N. Neopterin augmentation of tumor necrosis factor production. Immunol Lett 30:101–106, 1991.

29.

Hoffmann G, Frede S, Kenn S, Smolny M, Wachter H, Fuchs D, Grote J, Rieder J, Schobersberger W. Neopterin-induced tumor necrosis factor-alpha synthesis in vascular smooth muscle cells in vitro. Int Arch Allergy Immunol 116:240–245, 1998.

30.

Nakamura K, Kouro T, Kincade PW, Malykhin A, Maeda K, Coggeshall KM. Src homology 2-containing 5-inositol phosphatase (SHIP) suppresses an early stage of lymphoid cell development through elevated interleukin-6 production by myeloid cells in bone marrow. J Exp Med 199:243–254, 2004.

31.

Maeda K, Baba Y, Nagai Y, Miyazaki K, Malykhin A, Nakamura K, Kincade PW, Sakaguchi N, Coggeshall KM. IL-6 blocks a discrete early step in lymphopoiesis. Blood 106:879–885, 2005.

32.

Saito H, Sherwood ER, Varma TK, Evers BM. Effect of aging on mortality, hypothermia, and cytokine induction in mice with endotoxemia or sepsis. Mech Ageing Dev 124:1047–1058, 2003.

33.

Tateda K, Matsumoto T, Miyazaki S, Yamaguchi K. Lipopolysaccharide-induced lethality and cytokine production in aged mice. Infect Immun 64:769–774, 1996.

Inflammatory Biomarker,Neopterin,Suppresses B Lymphopoiesis for Possible Facilitation of Granulocyte Responses,Which Is Severely Altered in Age-Related Stromal-Cell–Impaired Mice,SCI/SAM

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