Levels of inhibitory mechanisms

Cytokine production (see Figure 1) can be regulated at the gene level (la), where promoters or inhibitors of transcription act, and at the mRNA level (lb), where the stability and translation of the message can be modulated by hormones, cytokines or drugs. Members of the MAP kinase family and serine-threonine kinase are among the factors involved in the signal transduction pathway for cytokine production and are therefore the target of drug intervention. In addition, the intracellular protein level can be affected by proteases (lc) needed to process propeptides into mature, functionally active polypeptides or to release cytokines from the cytoplasmic membrane. Once released, the biologically active amounts of a cytokine can be modulated by soluble ligands (2), in the form of nonreceptor cytokine-binding proteins (2a), autoantibodies (2b), soluble specific receptors (2c), and by proteolytic enzymes (2d). Soluble receptors can be derived from proteolytic cleavage of membrane-bound receptors (i.e. tumor necrosis factor a (TNFa) and interleukin 1 (IL-1) receptors), by alternative splicing of the mRNA coding for membrane receptors (i.e. sIL-4R), and by post-trans-lational modification (i.e. glycosyl phosphatidylinosi-

tol (GPI)-anchored receptors by removal of the signal peptide). All the soluble ligands with cytokine-bind-ing capacity potentially participate in the regulation of cytokine delivery and homeostasis. Whether their net effect is inhibition or enhancement of the cytokine action may depend on specific characteristics of the binding protein and on the kinetics of binding. As long as the cytokine is prevented from reaching membrane receptors, inhibition is maintained. However, soluble receptors and other soluble ligands can actually increase the concentration of cytokines in body fluids by increasing their stability and decreasing their proteolytic degradation. Upon dissociation from soluble ligands, biologically active cytokines can again reach and activate specific membrane receptors. Thus, soluble ligands can function as carriers of cytokines. Binding affinity therefore plays an important role in determining the relevance of soluble ligands in cytokine homeostasis. For instance, very high concentrations of soluble receptors are needed to effectively compete with membrane receptors when these receptors are associated with transducing subunits which increase their binding affinity (i.e. sIL-2Ra). In contrast, the soluble forms of single chain receptors (sIL-lR; sTNF-R) are strong competitors and lesser amounts of them are required.

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