Paracrine responses

From the earlier work discussed at the 1978 Cold Spring Harbor Meeting on Cell Proliferation there has developed a broad field concerned with the study of growth factors and hormones and their effects on cell growth and differentiation. This area is considered in more detail in Chapter 2 and is of enormous clinical importance for the treatment of cancer. As well as the work on peptide hormones much work has focused on the use of MCF-7 and ZR 75.1 cell lines which were isolated from human breast tumour tissue (Lippman et al., 1977 Engel et al., 1978). These cells respond to oestrogen treatment, but the system is not as simple as first thought and may involve paracrine responses (Leake, 1988). 

The factors which affect cells may be produced by the same cell as responds to them (an autocrine response shown by some tumour cells), or may be produced by a neighbouring cell type (a paracrine response mediated by the interleukins). It is sometimes only possible to distinguish autocrine and paracrine responses by cloning cells from a particular tissue, as a factor produced by one cell type may be processed by a second cell type before reacting with receptors on the first cell type. 

Transport in the blood is no longer a requisite for a hormonal response. Responses can occur after release of hormones into the interstitial fluid with binding to receptors in nearby ceUs, called paracrine control, or binding to receptors on the ceU that released the hormone, called autocrine control. A class of hormones shown to be synthesized by the tissue in which they act or to act in the local ceUular environment are the prostaglandins (qv). These ubiquitous compounds are derived from arachidonic acid [506-32-1] which is stored in the ceU membranes as part of phosphoHpids. Prostaglandins bind to specific ceUular receptors and act as important modulators of ceU activity in many tissues. 

Nearly all of the interleukins are soluble molecules (one form of IL-1 is cell associated). They promote their biological response by binding to specific receptors on the surface of target cells. Most interleukins exhibit paracrine activity (i.e. the target cells are in the immediate vicinity of the producer cells), although some display autocrine activity (e.g. IL-2 can stimulate the growth and differentiation of the cells that produce it). Other interleukins display more systematic endocrine effects (e.g. some activities of IL-1). 

Table 9.3 The range of cells expressing the IL-2 cell surface receptor. IL-2-stimulated growth and differentiation of these cells forms the molecular basis by which many aspects of the immune response are activated. It thus acts in an autocrine and paracrine manner to mobilize...

PDGF plays an important role in the wound healing process. It is released at the site of damage by activated platelets, and acts as a mitogen/chemoattractant for many of the cells responsible for initiation of tissue repair. It thus tends to act primarily in a paracrine manner. It also represents an autocrine/paracrine growth factor for a variety of malignant cells. 

The factors are secreted into the extracellular milieu where they diffuse and then act in a paracrine fashion on other cells (Fig. 27-1). Indeed, there is evidence that this type of paracrine support is necessary to sustain neurons as they extend their processes over long distances in the developing nervous system [2]. An analogous process, autocrine stimulation, occurs when a cell synthesizes and secretes a growth factor to which the cell itself is responsive. In this case, the cell provides its own trophic support. 

The humoral factors include numerous cytokines and growth factors, which act as classical endocrine, paracrine or autocrine regulators. Developing cells are sensitive to a range of such factors at all times during their maturation and, in the case of white blood cells, during their existence within the circulation. To ensure responsiveness during their development, cells must express on their surface a variety of receptors at different times. 

The GI system is responsible at its most basic level for providing a continual supply of water, electrolytes, minerals, and nutrients. This is achieved by a myriad of specialized cells and coordinated interplay of motility, secretion, digestion, absorption, blood flow, and lymph flow. These components are under elaborate control of the central and enteric nervous systems, endocrine and paracrine regulation of hormones. The highly complex nature of GI function is clearly illustrated by the estimate that 80 to 100 million neurons exist within the enteric nervous system, a number comparable to that found within the spinal column, hence described as a "second brain."171... 

PTHrP). The receptor signal is mediated by G proteins that activate adenylyl cyclase and the phosphatidylinositol-calcinm second-messenger system. Mntations of PTHRl are associated with abnormalities of development related to altered PTHrP ligand binding. PTHrP is a key paracrine peptide responsible for osteochondrogenesis dnring fetal development (55,56). 

The function of serotonin in enterochromaffin cells is not fully understood. These cells synthesize serotonin, store the amine in a complex with ATP and with other substances in granules, and release serotonin in response to mechanical and neuronal stimuli. This paracrine serotonin interacts with several 5-HT receptors in the gut. Some of the released serotonin diffuses into blood vessels and is taken up and stored in platelets. 

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