Cell source and inducers

Mononuclear phagocytes are the major cell source of IL-1. However every mature nucleated cell type examined has been shown to be capable of producing IL-1, including keratinocytes, dendritic cells, astrocytes, microglial cells, normal B lymphocytes, cultured T cell clones, natural killer cells, other leukocytes, fibroblasts, neutrophils, epithelial cells, endothelial cells and smooth muscle cells. Normal cells must be stimulated to produce IL-1. II.-1 production by macrophages can be triggered by a variety of proinflammatory stimuli, including bacterial cell wall products, LPS, microbial superantigens, zymosan, phorbol esters, muramyl dipeptide, antigens, mitogens, leukotrienes, activated complement components (C5a), immune complexes, ultraviolet irradiation, silica particles, viruses, parasites and other microorganisms. Agents that activate lymphocytes can stimulate macrophages to produce IL-1 either in response to direct cell interactions, or by

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Figure 1 Interleukin 1: from genes to proteins.

producing cytokines such as lymphotoxin, granulo-cyte-macrophage colony-stimulating factor (GM-CSF), or IL-1 itself, which can stimulate macrophages and other cells to produce more IL-1.

The production of IL-1 (3 and IL-lra in human monocytes is reciprocally regulated. In vitro studies by Arend and colleagues showed the production of both IL-1 p and IL-lra by LPS-stimulated monocytes. Monocytes cultured adherent to IgG-coated surfaces exhibited no IL-ip gene expression, but high levels of IL-lra due to enhanced transcription and prolonged mRNA stability. The mechanism of this differential regulation of IL-1 and IL-lra may involve cross-linking of different carbohydrate groups on the cell surface, resulting in differential signal transduction pathways. Other studies also suggest that production of IL-ip and IL-lra are differentially regulated by cytokines. For example, IL-4, IL-10 and transforming growth factor p (TGFp) decrease production of IL-ip, but can concomitantly increase synthesis of IL-lra in monocytes. Corticosteroids suppress the production of IL-la and IL-ip but have no effect on IL-lra. Studies of the kinetics of production of IL-1 generally reveal that IL-ip is made

Figure 1 Interleukin 1: from genes to proteins.

before IL-la, and IL-lra is made last. In addition, patients treated with IL-ip develop elevated plasma IL-lra levels indicating that even IL-1 induces IL-lra production.

Many cell types express all three IL-1 genes, but levels of IL-la, IL-ip and IL-lra vary widely. Kera-tinocytes express mostly IL-la and IL-lra. Human monocytes produce predominantly IL-13 while mouse macrophages produce mostly IL-la. During differentiation of monocytes into macrophages, production of IL-lra is upregulated while production of IL-ip is decreased. Thus IL-lra is a major product of tissue macrophages, particularly during disease. Most of the IL-1 activity found in the circulation is IL-ip whereas IL-la is more often detected on cell surfaces. Plasma concentrations of IL-ip in normal subjects are usually undetectable (<40pgml '), except in women after ovulation and in subjects after strenuous exercise. Normal human subjects have circulating levels of IL-lra in the range of 200-300 pg ml"1. Studies by Dinarello and coworkers showed that during experimental endotoxemia in humans, peak levels of 150-200 pg ml 1 of IL-1 p occurred at 3-4 h. In contrast, peak levels of 6000-8000 pg ml '

of IL-lra typically occurred after 4 h and remained high for another 8 h.

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