Cox

arachidonic acid COX 2

lipoxygenase

lipoxygenase

FIGURE 13 Synthesis and structures of some arachidonic acid metabolites. R may be choline, inositol, serine or ethanolamine. PG, prostaglandin; LT, leukotriene. The designations E2 or F2o, refer to substituents on the ring structure of the PG. The designations D4 and E4 refer to glutathione derivatives in thioester linkage at carbon 6 of LT.

Glucocorticoids and Cytokines

The large number of compounds designated as cyto-kines include one or more isoforms of the interleukins (IL-1 through IL-18), tumor necrosis factor (TNF), the interferons (IFN-a, -y), colony stimulating factor (CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), transforming growth factor (TGF), leukemia inhibiting factor, oncostatin, and a variety of cell- or tissue-specific growth factors. It is not clear just how many of these hormone-like molecules are produced, and not all have a role in inflammation. Two of these factors, IL-1y8 and TNFa are particularly important in the development of inflammation. The intracellular signaling pathways and biological actions of these two cytokines are remarkably similar. They enhance each other's actions in the inflammatory response and differ only in the respect that TNFa may promote cell death (apoptosis), whereas IL-1 does not.

Interleukin-1 is produced primarily by macrophages and to a lesser extent by other connective tissue elements, skin, and endothelial cells. Its release from macrophages is stimulated by interaction with immune complexes, activated lymphocytes, and metabolites of arachidonic acid, especially leukotrienes. IL-1 is not stored in its cells of origin but is synthesized and secreted within hours of stimulation in a response mediated by increased intracellular calcium and protein kinase C. IL-1 acts on many cells to produce a variety of responses, all of which are components of the inflammatory/ immune response. They are illustrated in Fig. 14. Many of the consequences of these actions can be recognized from personal experience as nonspecific symptoms of viral infection. TNFa is also produced in macrophages and other cells in response to injury and immune complexes, and it can act on many cells including those that secrete it. Secretion of both IL-1 and TNFa and mitosis mitosis

lysosomes

lysosomes

protein degradation (pain)

FIGURE 14 Effects of IL-1. PG, prostaglandin; LT, leukotriene.

their receptors are increased by some of the cytokines and other mediators of inflammation whose production they increase, so that an amplifying positive feedback cascade is set in motion. Some products of these cytokines also feed back on their own production in a negative way to modulate the inflammatory response. Glucocorticoids play an important role as negative modulators of IL-1 and TNFa by (1) inhibiting their production, (2) interfering with signaling pathways, and (3) inhibiting the actions of their products. Glucocorti-coids also interfere with the production and release of other pro-inflammatory cytokines as well, including IFN-y, IL-2, IL-6, and IL-8.

Production of IL-1 and TNFa and many of their effects on target cells are mediated by activation of genes by the transcription factor, nuclear factor kappa B (NF-kB). In the unactivated state NF-kB resides in the cytoplasm bound to the NF-kB inhibitor (I-kB). Activation of the signaling cascade by some tissue insult or the binding of IL-1 and TNFa to their respective receptors is initiated by activation of a kinase (IkK) that phosphor-ylates I-kB, causing it to dissociate from NF-kB and to be degraded. Free NF-kB is then able to translocate to the nucleus where it binds to response elements in genes that it regulates, including genes for the cytokines IL-1, TNFa,, IL-6, and IL-8 and for such enzymes as PLA2, COX2, and nitric oxide synthase (Fig. 15). IL-6 is an important pro-inflammatory cytokine that acts on the hypothalamus, liver, and other tissues, and IL-8 plays an important role as a leukocyte attractant. Nitric oxide is important as a vasodilator and may have other effects as well. Glucocorticoids interfere with the actions of IL-1 and TNFa by promoting the synthesis of I-kB, which traps NF-kB in the cytosol, and by interfering with the ability of NF-kB that enters the nucleus to activate target genes. The mechanism for interference with gene activation is thought to involve protein-protein interaction between the liganded glucocorticoid receptor and NF-kB. Glucocorticoids also appear to interfere with IL-1 or TNFa-dependent activation of other genes by the AP-1 transcription complex. In addition, cortisol induces expression of a protein that inhibits PLA2 and destabilizes the mRNA for COX2. It is noteworthy that many of the responses attributed to IL-1 may be mediated by prostaglandins or other arachidonate metabolites. For example, IL-1, which is identical with what was once

I-kB-P04

TNFa tissue insult IL-1 Cortisol prostaglandins thromboxanes leukotrienes

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