Inhibition of interleukin1

IL-l is a potent mediator of inflammation affecting the function of many different cell types. At least five different levels of regulation of IL-l activities have been documented.

IL-l receptor antagonist (IL-IRa), a glycoprotein of 22 000 molecular weight, is a member of the IL-l gene family and binds IL-1R type I, a receptor capable of transducing signals, with similar affinity to that of IL-la and IL-l(3. However, unique in cytokine biology, no signal is transduced upon Il.-lRa binding to IL-1R. It is speculated that no signal is transduced because IL-IRa fails to bind the IL-l receptor accessory protein (IL-lR-AcP), thus inhibiting the formation of the IL-l receptor hetero-dimer complex required for signal transduction. IL-IRa is produced by the same cells that secrete IL-l; however, the expression of IL-IRa is regulated by different types of stimuli including complexed IgG and anti-inflammatory cytokines. In addition, II.-1 and IL-IRa exist in various forms (i.e. secreted and intracellular). The actual extent of the inhibitory activity of IL-IRa in vivo is unclear. Due to the fact that occupancy of only a few membrane IL-1 type I receptors is sufficient to generate a biological response, the concentration of IL-IRa (compared to IL-l) needed to interfere with IL-l activity has to be at least 100 times higher.

IL-1R type II binds with high affinity both IL-1 [3 and IL-IRa. However, it lacks a cytoplasmic domain and does not transduce signals. Therefore, this type of receptor functions as a decoy, inhibiting II -1 (3 activities.

Both type I and type II IL-l reccptors exist in soluble form after proteolytic cleavage of the full length membrane forms. The rank of binding to type II IL-1 soluble receptor is IL-1 (3 > IL-lct > IL-IRa and for type I IL-l soluble receptor it is IL-1 Ra > IL-la > IL-1(3. IL-l soluble receptors with bound IL-l species do not have signaling capacity; instead, they act by decreasing the levels of biologically active IL-l.

Naturally occurring autoantibodies that bind IL-la (but not IL-ip) have been described in about 25%

Table 1 Mechanisms involved in cytokine inhibition

Level Process Mechanism

Cytokine synthesis and secretion Transcriptional regulation Transcription factors mRNA stability 3'-AU-rich motifs

Transcription/translation Hormones (e.g. corticosteroids)

Cytokines

Processing and release Proteases (e.g. metalloproteases)

Expression of membrane cytokine R Competition Nonsignaling receptors (e.g. IL-1R type II)

Interaction of cytokines with membrane R Interference Soluble cytokine R

Receptor antagonists (e.g. IL-1Ra) Nonreceptor cytokine-binding protein (e.g.

uromodulin) Anticytokine autoantibodies of normal individuals, and some of them have proved to neutralize IL-1 a in vitro. The prevalence of such autoantibodies is increased in some inflammatory autoimmune diseases (e.g. rheumatoid arthritis). Their function in vivo remains unclear but they could contribute to regulating the levels of bioactive IL-1 a so that disease activity may inversely correlate with the amounts of blocking autoantibodies.

The production of IL-IRa can be enhanced by antiinflammatory cytokines such as IL-4, IL-13, IL-10, and transforming growth factor (3 (TGF(3). These cytokines increase IL-IRa production while decreasing lipopolysaccharide (LPS)-induced IL-1 production in vitro. The levels of type II IL-1 soluble receptor are also increased in response to IL-4. Thus, the coordinate expression and upregulation of the receptor antagonist and of type II soluble receptor may regulate and decrease the responses to IL-1. In vivo, infusion of IL-4 results in the suppression of gene expression and synthesis of inflammatory cytokines while inducing high levels of IL-IRa and type II soluble receptor.

Large amounts of IL-la may exist at the intracellular level, both in the cytoplasm and in the nucleus, in the form of pro-IL-la which is processed by the interleukin-1 converting enzyme (ICE), in turn controlled by inhibitors. This is well documented in keratinocytes where pro-IL-la is thought to drive terminal cell differentiation. An intracellular form of IL-IRa (icIL-IRa) has also been documented in keratinocytes and monocytes, that is supposed to regulate pro-IL-la-driven cell proliferation and differentiation. IL-IRa, easily detectable in human serum, is also produced by hepatocytes, behaves as an acute-phase protein and probably is an important factor in host defense. Its monitoring could be useful in assessing inflammatory diseases.

Interestingly, several vaccinia strains of the poxviruses have encoded in their genome the capacity to secrete a soluble protein which binds to IL-1 (3 selectively and with high affinity. Although structurally different, this viral protein shares 33% homology with human IL-1 receptors at the amino acid level. The virus strains capable of releasing this protein are less virulent, and it is speculated that evolutionary selective pressure has favored the development of these strains because they are substantially less pathogenic, thus ensuring the survival of both host and virus. These data emphasize the importance of IL-1 in both protection and pathology. They stress the relevance of fine tuning the levels of bioactive agonistic IL-1 and explain the redundancy of the molecules implicated in its control.

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