title: 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.
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-alpha (TNF-alpha ), interleukin-6 (IL-6), and transforming growth factor-beta (TGF-beta) 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-alpha 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.
authors.affiliation: Department of Anatomy, Nihon University School of Medicine, 30-1 Ohyaguchi-Kamimachi, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Minami
authors.forename: Isao
authors.initials: I
authors.lastname: Tsuboi
authors.forename: Tomonori
authors.initials: T
authors.lastname: Harada
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Fukumoto
authors.forename: Masaki
authors.initials: M
authors.lastname: Hiramoto
authors.forename: Morimichi
authors.initials: M
authors.lastname: Koshinaga
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hirabayashi
authors.forename: Jun
authors.initials: J
authors.lastname: Kanno
authors.forename: Tohru
authors.initials: T
authors.lastname: Inoue
authors.forename: Shin
authors.initials: S
authors.lastname: Aizawa
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000166:cytology*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D038041:Lymphopoiesis; D051379:Mice; D038042:Myelopoiesis; D019798:Neopterin / Q000494:pharmacology / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D015850:Interleukin-6; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D019798:Neopterin