Harris R J, Pettitt A R, Schmutz C, Sherrington P D, Zuzel M, Cawley J C, Griffiths S D
Department of Haematology, University of Liverpool, Liverpool, United Kingdom.
J Immunol. 2000 Apr 1;164(7):3887-93. doi: 10.4049/jimmunol.164.7.3887.
The role of GM-CSF in B cell (patho)physiology is unclear. Although B cells can respond to GM-CSF, there is controversy concerning the extent to which various resting and activated B cell types can themselves produce this cytokine, and the possibility that it can function in an autocrine fashion has not previously been considered. The aim of the present study was to address these issues using hairy cells (HCs) and chronic lymphocytic leukemia cells, two intrinsically activated mature malignant B cell types (with activation being more uniform and more pronounced in HCs). Normal B cells were used for comparison. Using a number of techniques, we demonstrated the constitutive production of GM-CSF by all three cell types and showed that the cytokine was biologically active. GM-CSF mRNA and protein were increased after cell activation by PMA, and constitutive production of the cytokine was highest in HCs, suggesting that the level of GM-CSF production is influenced by cell activation. Because GM-CSF is known to be antiapoptotic for myeloid cells, we used blocking anti-GM-CSF Abs to examine the contribution of autocrinely produced cytokine to cell survival. The Abs produced marked reduction in the in vitro survival of HCs, chronic lymphocytic leukemia cells, and normal B cells by promoting apoptosis. Taken together, these findings suggest that, in combination with other known rescue factors, autocrinely produced GM-CSF may contribute to normal and malignant B cell survival in vivo.
粒细胞-巨噬细胞集落刺激因子（GM-CSF）在B细胞（病理）生理学中的作用尚不清楚。尽管B细胞能够对GM-CSF作出反应，但对于各种静息和活化的B细胞类型自身产生这种细胞因子的程度仍存在争议，并且此前尚未考虑其以自分泌方式发挥作用的可能性。本研究的目的是利用毛细胞（HCs）和慢性淋巴细胞白血病细胞这两种内在活化的成熟恶性B细胞类型（在HCs中活化更为一致且更为明显）来解决这些问题。使用正常B细胞作为对照。通过多种技术，我们证明了这三种细胞类型均可组成性产生GM-CSF，并表明该细胞因子具有生物学活性。经佛波酯（PMA）激活细胞后，GM-CSF的信使核糖核酸（mRNA）和蛋白质水平升高，且细胞因子的组成性产生在HCs中最高，这表明GM-CSF的产生水平受细胞活化的影响。由于已知GM-CSF对髓样细胞具有抗凋亡作用，我们使用抗GM-CSF阻断抗体来研究自分泌产生的细胞因子对细胞存活的作用。这些抗体通过促进细胞凋亡，显著降低了HCs、慢性淋巴细胞白血病细胞和正常B细胞在体外的存活率。综上所述，这些发现表明，自分泌产生的GM-CSF与其他已知的挽救因子共同作用，可能有助于体内正常和恶性B细胞的存活。
