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Neutropenia with impaired host defense against microbial infection in mice lacking androgen receptor

By Kuang-Hsiang Chuang, Saleh Altuwaijri, Gonghui Li, Jiann-Jyh Lai, Chin-Yi Chu, Kuo-Pao Lai, Hung-Yun Lin, Jong-Wei Hsu, Peter Keng, Ming-Chi Wu and Chawnshang Chang


Neutrophils, the major phagocytes that form the first line of cell-mediated defense against microbial infection, are produced in the bone marrow and released into the circulation in response to granulocyte-colony stimulating factor (G-CSF). Here, we report that androgen receptor knockout (ARKO) mice are neutropenic and susceptible to acute bacterial infection, whereas castration only results in moderate neutrophil reduction in mice and humans. Androgen supplement can restore neutrophil counts via stabilizing AR in castrated mice, but not in ARKO and testicular feminization mutant (Tfm) mice. Our results show that deletion of the AR gene does not influence myeloid lineage commitment, but significantly reduces the proliferative activity of neutrophil precursors and retards neutrophil maturation. CXCR2-dependent migration is also decreased in ARKO neutrophils as compared with wild-type controls. G-CSF is unable to delay apoptosis in ARKO neutrophils, and ARKO mice show a poor granulopoietic response to exogenous G-CSF injection. In addition, AR can restore G-CSF–dependent granulocytic differentiation upon transduction into ARKO progenitors. We further found that AR augments G-CSF signaling by activating extracellular signal-regulated kinase 1/2 and also by sustaining Stat3 activity via diminishing the inhibitory binding of PIAS3 to Stat3. Collectively, our findings demonstrate an essential role for AR in granulopoiesis and host defense against microbial infection

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Publisher: The Rockefeller University Press
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Provided by: PubMed Central

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  1. (2003). Abnormal mammary gland development and growth retardation in female mice and MCF7 breast cancer cells lacking androgen receptor.
  2. (1996). Activation of the human androgen receptor through a protein kinase A signaling pathway.
  3. (1988). Androgen and erythropoiesis: evidence for an androgen receptor in erythroblasts from human bone marrow cultures.
  4. (2005). Androgen receptor activation by G(s) signaling in prostate cancer cells.
  5. (1994). Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res.
  6. (2008). Androgen receptor functions in male and female physiology.
  7. (1994). Association of p72 tyrosine kinase with Stat factors and its activation by interleukin-3, interleukin-6, and granulocyte colony-stimulating factor.
  8. (1995). Chemokine binding and activities mediated by the mouse IL-8 receptor.
  9. (2002). Control of myeloid-specific integrin alpha Mbeta 2 (CD11b/CD18) expression by cytokines is regulated by Stat3-dependent activation of PU.1.
  10. (2001). CXCR2 deficiency confers impaired neutrophil recruitment and increased susceptibility during Toxoplasma gondii infection.
  11. (2005). Cytokine signals through STAT3 promote expression of granulocyte secondary granule proteins in 32D cells.
  12. (2003). Disruption of the estrogen receptor beta gene in mice causes myeloproliferative disease resembling chronic myeloid leukemia with lymphoid blast crisis.
  13. (1985). Effects of androgenic steroids on erythropoiesis.
  14. (1981). Effects of testosterone and 5 beta-androstanes on in vitro erythroid colony formation in mouse bone marrow.
  15. (2002). Evaluation of role of G-CSF in the production, survival, and release of neutrophils from bone marrow into circulation.
  16. (1999). From HER2/Neu signal cascade to androgen receptor and its coactivators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells.
  17. (2002). Generation and characterization of androgen receptor knockout (ARKO) mice: an in vivo model for the study of androgen functions in selective tissues.
  18. (1991). Granulocyte colony-stimulating factor and its receptor.
  19. (1994). Granulocyte colony-stimulating factor receptor signaling involves the formation of a three-component complex with Lyn and Syk protein-tyrosine kinases.
  20. (1994). Hematologic effects of androgens revisited: an alternative therapy in various hematologic conditions.
  21. (1999). Impaired antibacterial host defense in mice lacking the N-formylpeptide receptor.
  22. (1996). Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice.
  23. (1986). Methods for assessing exocytosis by neutrophil leukocytes. Methods Enzymol.
  24. (1994). Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization.
  25. (2007). Mice lacking three myeloid colony-stimulating factors (G-CSF, GM-CSF, and M-CSF) still produce macrophages and granulocytes and mount an inflammatory response in a sterile model of peritonitis.
  26. Multiple signals mediate proliferation, differentiation, and survival from the granulocyte colony-stimulating factor receptor in myeloid 32D cells.
  27. (1983). Physiologic mechanisms and the hematopoietic effects of the androstanes and their derivatives.
  28. (1998). Proliferation signaling and activation of Shc, p21Ras, and Myc via tyrosine 764 of human granulocyte colony-stimulating factor receptor.
  29. (1995). Protection of human polymorphonuclear leukocyte function from the deleterious effects of isolation, irradiation, and storage by interferon-gamma and granulocyte-colony-stimulating factor.
  30. (1986). Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells.
  31. (2005). Signal transducers and activators of transcription 3 augments the transcriptional activity of CCAAT/enhancer-binding protein alpha in granulocyte colony-stimulating factor signaling pathway.
  32. (2004). SOCS3 is a critical physiological negative regulator of G-CSF signaling and emergency granulopoiesis.
  33. (2004). SOCS3 is a physiological negative regulator for granulopoiesis and granulocyte colonystimulating factor receptor signaling.
  34. (2001). STAT-3 activation is required for normal G-CSF-dependent proliferation and granulocytic differentiation.
  35. (1996). STAT3 activation is a critical step in gp130-mediated terminal differentiation and growth arrest of a myeloid cell line.
  36. (2003). STAT3 deletion during hematopoiesis causes Crohn’s disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity.
  37. (2006). STAT3 governs distinct pathways in emergency granulopoiesis and mature neutrophils.
  38. (2002). STAT3 is a negative regulator of granulopoiesis but is not required for G-CSF-dependent differentiation.
  39. (2000). Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation.
  40. (2004). Subfertility and defective folliculogenesis in female mice lacking androgen receptor.
  41. (1999). Sustained receptor activation and hyperproliferation in response to granulocyte colony-stimulating factor (G-CSF) in mice with a severe congenital neutropenia/acute myeloid leukemia-derived mutation in the G-CSF receptor gene.
  42. (1990). The human N-formylpeptide receptor. Characterization of two cDNA isolates and evidence for a new subfamily of G-protein-coupled receptors.
  43. (1989). The kinetics of human granulopoiesis following treatment with granulocyte colony-stimulating factor in vivo.
  44. (1994). The murine interleukin 8 type B receptor homologue and its ligands. Expression and biological characterization.
  45. (1981). The role of the androgen receptor in erythropoiesis.
  46. The threshold of gp130-dependent STAT3 signaling is critical for normal regulation of hematopoiesis.
  47. (2007). Vasoactive intestinal peptide transactivates the androgen receptor through a protein kinase A-dependent extracellular signal-regulated kinase pathway in prostate cancer LNCaP cells.

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