Cellular mechanism of hormone action
Hormonal regulation of physiological cell turnover and apoptosisLipid Second Messengers File Size: Get a free 7 day subscription by clicking below! Download as many books as you like Personal use Cancel the membership at any time if not satisfied. A collection of more than recipes formulated to optimize brain health, boost memory, improve mood, sharpen the central nervous system, and brustwachstum creme. Depression, ADHD, memory loss, agitation: These may seem like inevitable byproducts of modern lives spent multitasking, not getting enough sleep, and operating on digital overload.
Physiological cell turnover plays an important role in maintaining normal tissue function and architecture. This is achieved by the dynamic balance of cellular regeneration and elimination, occurring periodically in tissues such as the uterus and mammary gland, or at constant rates in tissues such as the gastrointestinal tract and adipose tissue. Apoptosis has been identified as the prevalent mode of physiological cell loss in most tissues. Although recent studies have provided significant information on specific tissue systems, a clearly defined pathway that mediates cell turnover has not yet emerged for any tissue.
Several similarities exist among the various tissues with regard to the intermediates that regulate tissue homeostasis, enabling a better understanding of the general mechanisms involved in the process.
Here we review the mechanisms by which hormonal and cytokine factors mediate cell turnover in various tissues, emphasizing common themes and tissue-specific differences.
Tissue homeostasis is an important physiological phenomenon that ensures a dynamic balance between cell proliferation and cell death in the maintenance and regulation of normal tissue morphology and function Hsueh et al.
Tissue maintenance is a continuous process by which progenitor cells are recruited to differentiate into specific cell types competent in performing specialized functions, and unwanted cells are eliminated without affecting neighboring cells. The normal life span of a cell may vary between a few days and several years, depending on the cell type. Cell death has been broadly classified into two categories, necrosis and apoptosis Fawthrop et al.
There is ongoing debate as to the mutually exclusive nature of the two categories, and it seems possible that there are many subcategories with blurred distinctions. Nevertheless, cell death clearly accompanied by an inflammatory response, resulting from cell swelling, loss of plasma membrane integrity and leakage of cellular contents into the extracellular space can certainly be classified as necrotic Raffray and Cohen ; Wyllie et al.
On the other hand cell death which occurs in seemingly random fashion in isolated individual cells within healthy tissues, and more extensively at times during ontogeny, without triggering an inflammatory response, can be termed apoptotic Ellis et al. Apoptosis is an energy-requiring process that often involves altered expression of key cell proliferation and death-inducing genes.
Sometimes, however, it can be initiated by receptors that feed directly into cascades that activate constitutive proenzymes sufficient to kill. Apoptotic cell death is responsible for most of the developmental tissue modeling and has been documented in several cases of physiological cell loss Gosden and Spears ; Kerr et al. Examples are the classical clonal deletion of T and B cells during negative selection associated with an immune response and the hormonally regulated cyclic regression of the uterine endometrium Gosden and Spears ; Owen and Jenkinson ; Thompson The significance of physiological apoptosis and cell turnover is apparent from the diseases associated with loss of such homeostatic regulation Hetts ; Rudin and Thompson A defect in the apoptotic machinery has been implicated in autoimmune lymphoproliferative disorders Abbas ; Van Parijs et al.
Understanding the physiological regulation of apoptosis can potentially lead to new avenues for the diagnosis and treatment of a variety of diseases. Two important aspects of apoptosis should be borne in mind as one reads this review. First, it is a fact that many compounds and circumstances can provoke apoptosis. Furthermore, a particular agent may produce apoptosis in a given cell or tissue, but may not in another, or in a given cell at one time during its life history but not at another.
Whether a cell responds to such an agent by dying must therefore depend on the specific array of interactive molecular regulatory systems active in that cell at that time. To understand how any specific hormone regulates apoptosis and cell turnover, it will be necessary to understand more fully the details of how these systems work, interact, and are arrayed in the cells and tissues of interest.
For no hormone or cell system is this presently known in full. The reader will see, therefore, many apparent gaps, contradictory results, and paradoxes in the information below. Nevertheless, general patterns can often be discerned, and the direction in which further work is needed can be seen.
This report is not a proper place to evaluate this question, and we will just refer to cells dying non-necrotically as apoptotic, without prejudice as to the specific systems that carry out the process.
Certainly several major molecular players involved in regulation and execution of cell death have been identified: These are referred to when appropriate. The initiators of physiological cell turnover and apoptosis may include cellular environment, growth factors, cytokines and hormones, acting in autocrine, paracrine or endocrine fashion.
Here, we will focus on the influence of the endocrine system in maintaining tissue homeostasis in a healthy adult human being. Continuous tissue renewal by balancing cell division and cell deletion is mediated by circulating levels of specific hormones Kiess and Gallaher ; Martimbeau and Tilly ; Tenniswood et al. Additionally, hormonal availability also determines the expression of growth factors and cytokines, which modulate cell turnover in target tissues. Endocrine gland functions and secretions are also subject to regulation via apoptosis of hormone-synthesizing cells, as is observed in the adrenal gland when deprived of adrenocorticotropic hormone.
Table 1 lists some of the proliferative and apoptotic actions of individual hormones in hormone-responsive tissues. In the process of developing and maintaining a normal immune system, T cells undergo a rigorous selection process in the thymus. A complex balance of factors, both extracellular and intracellular, leads to proper selection of mature thymic lymphocytes for a normal immune system.
This selection is dependent on the avidity of the T-cell receptor TCR for autologous antigen presented on major histocompatibility complex MHC molecules Jameson et al.
It is not clear how the same signaling pathway, mediated by TCR, can lead to both survival and apoptosis. The role of other regulators, including hormonal signals, in thymocyte deletion is being actively investigated Iwata et al.
Glucocorticoids GCs have long been known to have profound effects on the immune system, a classical response being the thymic involution that promptly follows administration of pharmacological amounts of GCs Dougherty ; Ingle Several studies have demonstrated that immature DP thymocytes are preferentially susceptible to GC-evoked apoptosis Ucker et al. In conditions of physiological stress, increased circulating glucocorticoids lead to thymic involution Tarcic et al.
Thus the massive apoptotic cell death in the thymus that is associated with T-cell selection appears to be under the control of corticosteroid hormones. In tissue culture, lymphoid cells selected for GC resistance often show loss of, or mutant, dysfunctional GR.
Thymocytes of transgenic mice with deliberately mutated GR show in vitro GC resistance Kellendonk et al. Mice expressing thymus-specific antisense GR transcripts GR-TKO mice exhibited loss of double-negative thymocytes, indicating the importance of GC in double-negative thymocyte survival and maturation to the DP stage King et al.
It has been proposed that GCs also are important mediators of death by neglect, which is associated with apoptotic deletion of thymocytes lacking functional TCR Cohen and Duke ; Sprent et al.
In support of this hypothesis, metyrapone, an inhibitor of GC synthesis, increased thymocyte recovery in fetal thymus organ cultures of thymi lacking functional MHC expression King et al.
In addition, GR-TKO mice are prone to thymomas derived from TCR minus cells, presumably owing to disabled apoptosis, and survival of thymocytes that normally would have been expunged via the death by neglect pathway King et al. Thus the interaction of TCR with antigen-presenting MHC molecules provides a protective signal that excludes them from apoptosis, in essence rendering them corticosteroid resistant Vacchio and Ashwell ; Vacchio et al.
Negative selection involves thymocytes that have escaped GC-evoked apoptosis through the default pathway, but have such high TCR avidity for MHC antigen that it forces cell death Sprent et al. It has been suggested that this threshold is determined by GC levels and thus that inhibition of GC production lowers the threshold of avidity beyond which negative selection ensues Iwata et al. This is consistent with the hypothesis that GCs are required to antagonize TCR-mediated apoptosis to facilitate positive selection of low to moderately avid TCR.
Mutual antagonism between activation-induced and GC-induced apoptotic pathways has also been demonstrated in vitro in T-cell hybridomas Zacharchuk et al. Thymocytes from these mice show GC resistance, and the distribution of thymocyte subtypes has been disrupted from failure of the normal selective turnover process. While the full mechanisms of GC-mediated regulation of thymocyte apoptosis are still being investigated, a general model has developed Fig.
Glucocorticoid regulation of thymocyte selection: The thymus itself is an endocrine organ and although the major source of circulating GCs is the adrenal gland, GCs are also produced locally in thymic epithelial cells, which are in direct contact with cortical DP immature thymocytes Vacchio et al.
In contrast to the adrenal gland, intrathymic corticosteroid production is maximal in the neonatal period, when thymocyte differentiation is at its peak Vacchio et al. GC levels in the thymic environment are therefore sufficient to mediate a normal apoptotic signal in the neonate.
In adults, adrenally derived steroids make up a significant fraction of the steroids contributing towards regulation of thymocyte numbers. It has been suggested that thymic CRF may have paracrine effects on immune function Aird et al. Thymosin, a peptide product of thymic stromal cells, abets thymocyte resistance to GCs and, along with a variety of thymic hormones, affects tissue turnover Baumann et al.
GC-evoked thymocyte apoptosis had been extensively studied for the elucidation of the molecular events preceding cell death Distelhorst ; Thompson Studies of isolated thymocytes and leukemic lymphoblasts in culture undergoing GC-evoked T-cell death helped define the classical morphological features of apoptosis.
Biochemically, these cells show altered expression of the oncogenes c- jun and c- myc , morphological changes, chromatin condensation, caspase and endonuclease activation, and DNA fragmentation Cohen and Duke ; Martins and Aguas ; Thompson et al. Cyclic AMP alone can also evoke apoptosis of thymocyte cell lines in culture. How this pathway interacts with the GC-mediated activation of GR-induced transcriptional responses is not well understood and is being intensely studied. In normal mouse thymocytes, GC-evoked apoptosis is linked to the generation of ceramides via the sequential production or activation of phosphoinositide-specific phospholipase C PI-PLC , diacyl glycerol DAG , protein kinase C and acidic sphingomyelinase aSMase Cifone et al.
The aSMase-dependent apoptotic pathway is apparently distinct from the pdependent pathway, since p53 and aSMase knockout mice exhibit distinct tissue-specific sensitivity to radiation-induced apoptosis Santana et al. Thymocytes from mice deficient in p53 exhibit normal sensitivity to GC-induced apoptosis; however, no reports are available on the susceptibility of aSMase-deficient thymocytes to GCs.
Acid SMase activation appears to mediate downstream activation of caspases, since inhibition of intermediate steps in the pathway blocks caspase activation in parallel with prevention of apoptosis Cifone et al. Caspase activity can be detected in immature DP thymocytes that are subject to apoptotic selection, but not in double-negative or mature thymocyte populations Jiang et al.
In recent years, mice generated by targeted disruption of individual caspase genes have yielded important information on their role in normal thymocyte development and selection Colussi and Kumar Mice deficient in caspase 1, 2, 3 or 9 exhibit normal development and distribution of thymocyte subpopulations Colussi and Kumar , and refs. GC-evoked apoptosis of thymic T cells is dependent on caspase 9 but not on caspase 3 activation, since thymocytes from caspase 3 knockout mice are normal Kuida et al.
Corresponding peripheral thymocytes are resistant to both stimuli, suggesting a significant difference in the apoptotic pathways activated in cells from individual compartments Colussi and Kumar Cell-specific differences in the recruitment of individual caspases have been reported in different subsets of isolated normal mouse T lymphocytes and T-cell lines when triggered to undergo apoptosis by the same stimulus Sarin et al.
Thus, great diversity exists in the recruitment of individual caspases by various apoptotic pathways. Deciphering the significance of their selective induction will be instrumental in fully understanding the physiological basis of thymic selection.
The prostate and testis involute upon deprivation of hormonal survival factors, e. A majority of reports describing involution of these tissues focus on apoptosis associated with non-physiological hormone ablation; however, in the intact animal there is some degree of spontaneous physiological cell turnover and apoptosis, which may also be hormonally regulated Huckins ; Russell and Clermont ; Sinha Hikim and Swerdloff Spermatogenesis occurs in the seminiferous tubules in the presence of testosterone secreted by the Leydig cells of the testis and gonadotropic hormones secreted by the anterior pituitary Means et al.
Beginning at puberty and continuing through life thereafter, the germinal epithelial cells continually proliferate and differentiate into spermatozoa in the presence of these hormones.
During specific stages of spermatogenesis, however, there is significant loss of developing germinal cells, but not Leydig or Sertoli cells Hsueh et al. In an early study, morphological features of physiological cell death during various stages of spermatogenesis in rats were similar to death associated with hypophysectomy, and included condensed chromosomes and nuclear distortion Huckins The authors noted that in normal as well as hypophysectomized rats, the same types of germinal cells were undergoing death, but with a marked difference in frequency.
Although these early studies report the death as necrotic, subsequent studies have determined that a majority of cell death is apoptotic Blanco-Rodriguez and Martinez-Garcia ; Hsueh et al.
The reason for spermatogonial degeneration is not well understood, but the ratio of spermatogonia to Sertoli cells may be a contributing factor, with survival of an optimal number of germ cells that can be sustained by Sertoli cells Blanco-Rodriguez and Martinez-Garcia ; Huckins Loss of spermatogonia may also be a mechanism to eliminate cells with defective chromosomes Blanco-Rodriguez and Martinez-Garcia ; Huckins Under conditions of gonadotropic hormone deprivation, such as after hypophysectomy, massive apoptosis reduces the pool of somatic Sertoli and Leydig cells as well as germ cells Tapanainen et al.
Testicular involution can be prevented by gonadotropin replacement, supporting the hypothesis that follicle-stimulating hormone FSH and luteinizing hormone LH prevent cell death in addition to supporting testicular cell differentiation and proliferation Hsueh et al.
Replenishment of testosterone by promoting Leydig cell function and survival also has a protective effect on germ cell survival Tapanainen et al. It has been proposed that Sertoli cells express FasL and cause apoptosis of Fas-expressing germ cells Lee et al. Another study Woolveridge et al. Changes in expression were analyzed in a mixed cell population from testis by Western blotting; hence it is difficult to interpret how they relate to apoptosis of individual cells or types of cells.
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