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ORIGINAL RESEARCH ARTICLE

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

Akihiro Minami^*, Isao Tsuboi^*,1, Tomonori Harada^*, Toshitaka Fukumoto^*, Masaki Hiramoto^*, Morimichi Koshinaga^*, Yoko Hirabayashi, Jun Kanno, Tohru Inoue and Shin Aizawa^*

^* Department of Anatomy, Nihon University School of Medicine, Tokyo 173-8610, Japan; Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Science, Tokyo 158-8501, Japan; and Center for Biological Safety and Research, National Institute of Health Science, Tokyo 158-8501, Japan

To whom requests for reprints should be addressed at ¹ Department of Anatomy, Nihon University School of Medicine, 30–1 Ohyaguchi-kamimachi, Itabashiku, Tokyo 173-8610, Japan. E-mail: tsuboi{at}med.nihon-u.ac.jp

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- (TNF- ), interleukin-6 (IL-6), and transforming growth factor-ß (TGF-ß) 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- 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.

Key Words: neopterin • B lymphopoiesis • stromal-cell–impaired mouse • subline of senescence-accelerated mice • aging