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hormonally regulated. That a proper balance between cell death and survival-promoting proteins is critical to achieve Transgenic mice expressing high levels of the BclxL or this physiological apoptotic wave at an early stage of Bcl2 proteins in the male germinal cells show a highly testicular germinal cell differentiation is substantiated by abnormal adult spermatogenesis accompanied by the finding of a comparable syndrome in mice defective sterility. This appears to result from the prevention of in the bax gene (Knudson et al., 1995). This early an early and massive wave of apoptosis in the testis, apoptotic wave of germ cells during establishment of which occurs among germinal cells during the first spermatogenesis may be required to maintain a proper round of spermatogenesis. In contrast, sporadic cell number ratio between maturing germ cells and Sertoli apoptosis among spermatogonia, which occurs in nor-cells. An intricate relationship involving a constant modumal adult testis, is not prevented in adult transgenic lation of activity and exchange of differentiation signals mice. The physiological early apoptotic wave in the indeed exists between these two cell types (reviewed in testis is coincident, in timing and localization, with a Jegou, 1993) from the first stage of spermatogenesis, and temporary high expression of the apoptosis-promoting its perturbation may extend to the life-long process of protein Bax, which disappears at sexual maturity. mature spermatogenesis. The critical role played by the intracellular balance, probably hormonally controlled, of the BclxL and Bax proteins (Bcl2 is apparently not expressed in normal Results mouse testis) in this early apoptotic wave is shown byMale transgenic mice expressing Bcl2 or the occurrence of a comparable testicular syndrome in overexpressing BclxL in their germinal cells are mice defective in the bax gene. The apoptotic wave sterile and display marked alterations in the late appears necessary for normal mature spermatogenesis stages of spermatogenesis to develop, probably because it maintains a critical cellMice bearing a human bcl2 or a human bclx transgene number ratio between some germinal cell stages and placed under the control of the promoter of the murine Sertoli cells, whose normal functions and differentihousekeeping phosphoglycerate kinase-1 (pgk-1) gene ation involve an elaborate network of communication.were generated. One male and four female founders Keywords: apoptosis/germinal cells/spermatogenesis/ bearing a bcl2 transgene were obtained. The male (T41) transgenic was sterile and one of the females (T56) showed a lack of vaginal opening at sexual maturity. The ovaries of this founder female were, however, functional, since, when grafted onto ovariectomized normal female mice, they

Monocytes are considered to be precursor cells of the mononuclear phagocytic system, and macrophages are one of the leading members of this cellular system. Macrophages play highly diverse roles in maintaining an organism’s integrity by either directly participating in pathogen elimination or repairing tissue under sterile inflammatory conditions. There are different subpopulations of macrophages and each one has its own characteristics and functions. In this review, we summarize present knowledge on the polarization of macrophages that allows the generation of subpopulations called classically activated macrophages or M1 and alternative activated macrophages or M2. Furthermore, there are macrophages that their origin and characterization still remain unclear but have been involved as main players in some human pathologies. Thus, we also review three other categories of macrophages: tumor-associated macrophages, CD169+ macrophages, and the recently named TCR+ macrophages. Based on the literature, we provide information on the molecular characterization of these macrophage subpopulations and their specific involvement in several human pathologies such as cancer, infectious diseases, obesity, and asthma. The refined characterization of the macrophage subpopulations can be useful in designing new strategies, supplementing those already established for the treatment of diseases using macrophages as a therapeutic target.

Approximately half of the neurons produced during embryogenesis normally die before adulthood. Although target-derived neurotrophic factors are known to be major determinants of programmed cell death--apoptosis--the molecular mechanisms by which trophic factors interfere with cell death regulation are largely unknown. Overexpression of the bcl-2 proto-oncogene in cultured sympathetic neurons has now been shown to prevent apoptosis normally induced by deprivation of nerve growth factor. This finding, together with the previous demonstration of bcl-2 expression in the nervous system, suggests that the Bcl-2 protein may be a major mediator of the effects of neurotrophic factors on neuronal survival.

The murine TNF-a gene was expressed under the control of the human surfactant protein SP-C promoter in transgenic mice. A number of the SP-C TNF-a mice died at birth or after a few weeks with very severe lung lesions. Surviving mice transmitted a pulmonary disease to their offspring, the severity and evolution of which was related to the level of TNF-a mRNA in the lung; TNF-a RNA was detected in alveolar epithelium, presumably in type II epithelial cells.In a longitudinal study of two independent mouse lines, pulmonary pathology, at 1-2 mo of age, consisted of a leukocytic alveolitis with a predominance of T lymphocytes. Leukocyte infiltration was associated with endothelial changes and increased levels of mRNA for the endothelial adhesion molecule VCAM-1. In the following months, alveolar spaces enlarged in association with thickening of the alveolar walls due to an accumulation of desmin-containing fibroblasts, collagen fibers, and lymphocytes. Alveolar surfaces were lined by regenerating type H epithelial cells, and alveolar spaces contained desquamating epithelial cells in places. Platelet trapping in the damaged alveolar capillaries was observed. Pulmonary pathology in the SP-C TNF-a mice bears a striking resemblance to human idiopathic pulmonary fibrosis, in which increased expression of TNF-a in type II epithelial cells has also been noted. These mice provide a valuable animal model for understanding the pathogenesis of pulmonary fibrosis and exploring possible therapeutic approaches. (J. Clin. Invest. 1995. 96:250-259.)