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SP0092 Regulation of neutrophil apoptosis during acute inflammation – a role for the bcl-2 family of apoptosis-associated genes
  1. B Walzog,
  2. P Weinmann,
  3. P Gaehtgens
  1. Physiology, Freie Universität Berlin, Berlin, Germany

Abstract

Introduction The life-span of circulating polymorphonuclear neutrophils (PMN) is relatively short when compared to other leukocytes but it can be further shortened by accelerating apoptosis. This is thought to be critical for the control of acute inflammation since apoptosis allows the “silent” elimination of emigrated PMN and thereby prevents uncontrolled tissue damage. This study was undertaken to elucidate the mechanisms which determine the life-span of emigrated PMN during acute inflammation.

Methods Apoptosis of isolated human PMN was investigated by (1) analysis of DNA content, (2) detection of DNA degradation, (3) analysis of nuclear morphology, and (4) measurement of CD16 expression on the cell surface. Gene expression was analysed by semi-quantitative RT-PCR and western blotting technique. Intraperitoneal thioglycollate injection in mice was used as an in vivo model for acute inflammation.

Results Leukocyte adhesion molecules of the β2 integrin family (CD11/CD18) which are critically involved in the recruitment of PMN to sites of inflammation were found to potentiate TNFα-induced apoptosis of human PMN within 4 h and 8 h after stimulation. The effect required aggregation of the β2 integrin Mac-1 (CD11b/CD18) and was independent of Fc receptors. An enhancement of apoptosis was also observed after migration of PMN through an endothelial cell monolayer which stained positively for ICAM-1, the ligand for the β2 integrins LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) suggesting that PMN emigration promotes apoptosis. This was confirmed using an in vivo model of acute inflammation in mice. Moreover, inflammatory, i.e. emigrated PMN showed a differential expression of apoptosis-associated genes of the bcl-2 family when compared to circulating PMN: Whereas the pro-apoptotic factor bax-alpha was up-regulated, the expression of the anti-apoptotic bcl-XL was down-regulated in emigrated PMN. Since the bcl-2 family plays an important role in the regulation of apoptosis, this shift of balance between anti- and pro-apoptotic factors may be responsible for the enhancement of apoptosis in inflammatory PMN.

Conclusions The present study suggests a physiologically relevant mechanism for the control of acute inflammation by promoting the turnover of previously emigrated PMN. This mechanism which involves the bcl-2 family of apoptosis-associated genes may be critical to subside local inflammatory processes in vivo.

References

  1. Walzog B, Jeblonski F, Zakrzewicz A, Gaehtgens P. FASEB J. 1997;11:1177–86

  2. Weinmann P, Gaehtgens P, Walzog B. Blood 1999;93:3106– 15

  3. Walzog B, Gaehtgens P. News Physiol Sci. 2000;15:107–13

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