Autocrine responses

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. 

M7. Manes, S., Llorente, M., Lacalle, R. A., Gomez-Mouton, C., Kremer, L., et al., The matrix metalloproteinase-9 regulates the insulin-like growth factor-triggered autocrine response in DU-145 carcinoma cells. J. Biol. Chem. 274, 6935—6945 (1999). 

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. 

IFN-y also directly modulates the immune response by affecting growth, differentiation and function of both T- and B-lymphocytes. These effects are quite complex and are often influenced by additional cytokines. IFN-y acts as a growth factor in an autocrine manner for some T cell sub-populations, and it is capable of suppressing growth of other T cell types. It appears to have an inhibitory effect on development of immature B-lymphocyte populations, but it may support mature B cell survival. It can both up-regulate and down-regulate antibody production under various circumstances. 

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...

Figure 9.3 Activation of T-cells by interaction with macrophage-displayed antigen. Activation results in IL-2 production, which acts in an autocrine manner to stimulate further T-cell growth and division. IL-2 thus represents the major regulatory molecule responsible for stimulation of cell-mediated immunity. Note that it was initially believed that binding of presented antigen alone was insufficient to trigger T-cell activation. It was thought that co-stimulation with IL-1 was reguired. However, the assay used to detect the co-stimulation was found not to be specific for IL-1 alone. The role of IL-1 as a co-stimulator of T-cell activation is now believed to be minimal at most...

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. 

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. 

NGF also has actions within the CNS, although it is not particularly abundant in the CNS. Its synthesis appears to be largely restricted to the hippocampus and neocortex, and even in these regions it is present at relatively low concentrations relative to the other neurotrophins. The most prominent population of NGF-responsive neurons expressing TrkA are the basal forebrain cholinergic neurons. The principal projections of these neurons are to the hippocampus and cortex, which conforms with the concept that NGF acts as a target-derived trophic factor in the CNS, just as it does in the peripheral nervous system (PNS). NGF also acts on a subpopulation of cholinergic neurons within the striatum. These interneurons express the NGF receptor, TrkA, and respond to NGF. However, they do not appear to rely entirely on NGF for their survival, and the specific actions of NGF on this neuronal population have not been clearly defined. NGF may also have autocrine actions in the CNS, as some neuronal populations have been identified that express both TrkA and NGF. 

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. 

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