Proliferation Autocrine effects

Hormones transfer signals by migrating from their site of synthesis to their site of action. They are usually transported in the blood. In this case, they are said to have an endocrine effect (1 example insulin). By contrast, tissue hormones, the target cells for which are in the immediate vicinity of the glandular cells that produce them, are said to have a paracrine effect (2 example gastrointestinal tract hormones). When signal substances also pass effects back to the cells that synthesize them, they are said to have an autocrine effect (3 example prostaglandins). Autocrine effects are often found in tumor cells (see p. 400), which stimulate their own proliferation in this way. 

Tamoxifen decreases the rate of proliferation of breast cancer cells in vitro by inhibiting the estrogen-dependent production of specific proteins and growth factors that exert autocrine effects on cell division. Antiandrogenic compounds antagonize the effects of testosterone and are of value in the treatment of hirsutism and other masculinizing syndromes. 

IL-2 acts as a critical autocrine growth factor for T-cells, and the magnitude of the T-cell response is largely dependent upon the level of IL-2 produced. IL-2 also serves as a growth factor for activated B-lymphocytes. In addition to promoting proliferation of these cells, IL-2 (as well as some other interleukins) stimulates enhanced antibody production and secretion. In this way, it effectively potentates the humoral immune response. 

The direct effects opioid and opioidlike peptides exhibit on cells of the immune system is both varied and, in some instances, contradictory, depending on which receptor subtype is being studied. Mu and kappa receptors generally affect immunofunction in a suppressive manner, where delta receptors tend to express immunostimulation [82-85]. However, selected delta antagonists have shown to elicit suppressive effects on B-cell proliferation, NK cell activity, and T-helper cell cytokine production [86]. The alteration of leukocyte function via opioid receptors will be discussed highlighting specific cell subtype immunomodulation. Endorphin shows a inhibitory effect on splenocyte proliferation through central and peripheral autocrine/paracrine pathways [87]. 

Fig. 4. Schematic model of the mechanisms of oestrogen control of cell proliferation. Three different mechanisms are illustrated. In (1) the interaction of oestrogen (E) with ER leads to increased transcription of genes whose products are directly involved in the control of cell replication. The mechanism illustrated in (2) postulates that oestrogens modulate the production of autocrine growth factors which in turn bind to growth factor receptors at the cell surface and mitogenesis occurs as a consequence of growth factor-activated metabolic pathways. The underlying hypothesis in (3) is that cells are under inhibitory (I) control by undefined molecules in the extracellular fluid and that oestrogens block the effects of these inhibitory molecules.

A further issue is the effect of PGs on the structural cells present in the airway wall. Asthma is characterized by increased smooth muscle mass (64). PGs could potentially affect the rate of proliferation and/or apoptosis of these cells. Some information is available from in vitro studies. Hirst et al. (77) have shown that various ECM proteins, such as collagen and fibronectin, have the capacity to affect ASM proliferation. Johnson et al. (30) have reported that ECM proteins secreted by asthmatic ASM, which likely include PG, enhanced ASM proliferation in an autocrine fashion. We have obtained some preliminary data showing that human ASM cells grown on decorin matrices show decreased proliferation (28). Finally, the interaction between TGF-p and decorin may be important in the asthmatic airway wall (60). TGF-p is increased in the asthmatic airway wall (78) and plays an important role in asthmatic airway inflammation. Hence, the effect of changes in PG deposition in the airway wall in asthma could have a number of important consequences on asthmatic airway pathophysiology. 

Yamaguchi and Ruoslahti (71) first noted that overexpression of decorin in Chinese hamster ovary cells reduced their rate of proliferation and density at saturation. This effect was subsequently attributed to the direct binding and inactivation by decorin of the transforming growth factor-(3 (TGF-p) that was considered to be an autocrine stimulator of cell proliferation in these cultures (72). Biglycan was also reported to bind to TGF-p in the solid-phase competition assay system used in this study. 

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