The principal anti-inflammatory cytokines and cytokine inhibitors are listed in Tables 1, 2. The functional definition of an anti-inflammatory cytokine is the ability of the cytokine to inhibit the synthesis of IL-1, tumor necrosis factor (TNF), and other major proinflammatory cytokines.
Table 1: Cytokines with anti-inflammatory activities
|Il-1ra||Specific inhibitor of IL-1α and IL-1β mediated cellular activation at the IL-1 cellular receptor level|
|IL-4||Promotes Th2 lymphocyte development; inhibition of LPS-induced proinflammatory cytokines synthesis|
|IL-6||Inhibition of TNF and IL-1 production by macrophages|
|IL-10||Inhibition of monocyte/macrophage and mrutrophil cytokine production and inhibition of TH1-type lymphocyte responses|
|IL-11||Inhibits proinflammatory cytokines response by monocyte/macrophages and promotes Th2 lymphocyte response|
|IL-13||Shares homology with IL-4 and shares IL-4 receptor; attenuation of monocyte/macrophage function|
|TGF-β||Inhibition of monocyte/macrophage MHC, class II expression and proinflammatory cytokines synthesis|
Table 2: Soluble Cytokin Receptors With Anti-inflammatory Activities
|Solube receptor||Major Activities|
|Solube TNF receptor p55 (sTNFRI or sTNFRp55)||Binds to TNF trimers in the circulation, preventing membrane-bound TNF receptor-TNF ligand interactions|
|Solube TNF receptor p75(sTNFRII or sTNFRP75)||Binds to TNF trimers in the circulation, preventing membrane-bound TNF receptor-TNF ligand interactions|
|Soluble IL-1 receptor type 2 (sIL-1RII)||Binds to circulating IL-1 ligands in the plasma, preventing IL-1β from binding to the IL-1 receptor type 1|
|Membrane-bound IL-1 receptor type 2 (mIL-1RII)||Decoy receptor that lacks intracellular signaling function and competes with type 1 IL-1R for IL-1 ligand binding at the cell membrane|
|IL-18 binding protein (IL-18BP)||Solube extracellular domain of IL-18 receptor that function as a decoy receptor and binds circulating IL-18|
IL-1ra is a 152-amino-acid protein that functions as a specific inhibitor of the two other functional members of the IL-1 family, IL-1a and IL-1 b. IL-1ra blocks the action of IL-1a and IL-1b functional ligands by competitive inhibition at the IL-1 receptor level. IL-1ra binds with equal or greater affinity than does IL-1a and IL-1 b to the type 1 (80 kd) membrane-bound IL-1 receptor. IL-1ra does not bind with high affinity to the type II (68 kd) IL-1 receptor.
IL-1ra is produced by monocytes and macrophages and is released into the systemic circulation in >100-fold excess than either IL-1a or IL-1 b after lipopolysaccharide (LPS) stimulation in human volunteers. The synthesis of IL-1ra and IL-1 b are differentially regulated at their own promoter sites. Although bacterial LPS stimulates the synthesis of both IL-1b and IL-1ra, other stimuli cause differential release of IL-1ra and IL-1 b. The anti-inflammatory cytokines IL-4, IL-6, IL-10, and IL-13 inhibit the synthesis of IL-1 b, yet they stimulate the synthesis of IL-1ra.
Because IL-1 is such a prominent proinflammatory cytokine in a multitude of systemic inflammatory states, IL-1ra has been extensively studied in clinical trials as a specific IL-1 inhibitor. Despite convincing evidence that IL-1 plays an important role in the pathogenesis of bacterial sepsis, the results of IL-1ra therapy in large phase III clinical trials for severe sepsis have been disappointing. Nonetheless, IL-1ra continues to be a promising new treatment for the management of patients with refractory forms of rheumatoid arthritis.
IL-4 is a highly pleiotropic cytokine that is able to influence Th cell differentiation. Early secretion of IL-4 leads to polarization of Th cell differentiation toward Th2-like cells. Th2-type cells secrete their own IL-4, and subsequent autocrine production of IL-4 supports cell proliferation. The Th2- cell secre-infections is not adequately defined and will necessitate additional clinical investigation. IL-4 is able to affect a variety of structural cells. It can potentiate proliferation of vascular endothelium and skin fibroblasts yet decrease proliferation of adult human astrocytes and vascular smooth muscle cells. In addition, IL-4 induces a potent cytotoxic response against tumors. In a study of 63 patients with stage IV non-small cell lung cancer, data on treatment with recombinant human IL-4 seemed to suggest a possible dose-related response. IL-4 may act by stabilizing disease and modifying tumor growth rates in addition to inducing tumor shrinkage and cell death without causing severe side effects, suggesting a possible adjuvant role for IL-4 in the treatment of malignant diseases.
IL-6 has long been regarded as a proinflammatory cytokine induced by LPS along with TNF-a and IL-1. IL-6 is often used as a marker for systemic activation of proinflammatory cytokines. Like many other cytokines, IL-6 has both proinflammatory and anti-inflammatory properties. Although IL-6 is a potent inducer of the acute-phase protein response, it has anti-inflammatory properties as well. IL-6, like other members of the gp130 receptor ligand family, acts predominantly as an anti-inflammatory cytokine. IL-6 down-regulates the synthe-sis of IL-1 and TNF.
IL-6 attenuates the synthesis of the proinflammatory cytokines while having little effect on the synthesis of anti-inflammatory cytokines such as IL-10 and transforming growth factor- b (TGF- b). IL-6 induces the synthesis of glucocorticoids and promotes the synthesis of IL-1ra and soluble TNF receptor release in human volunteers. At the same time, IL-6 inhibits the production of proinflammatory cytokines such as GM-CSF, IFN- g, and MIP-2. The net result of these immunologic effects place IL-6 the anti-inflammatory cytokine group.
IL-10 is the most important anti-inflammatory cytokine found within the human immune response. It is a potent inhibitor of Th1 cytokines, including both IL-2 and IFN- g. This activity accounts for its initial designation as cytokine synthesis inhibition factor. In addition to its activity as a Th2 lymphocyte cytokine, IL-10 is also a potent deactivator of monocyte/macrophage proinflammatory cytokine synthesis. After engaging its high-affinity 110-kd cellular receptor, IL-10 inhibits monocyte/macrophage-derived TNF-a, IL-1, IL-6, IL-8, IL-12, granulocyte colony-stimulating factor, MIP-1 a, and MIP-2a.
IL-11 has been shown to attenuate IL-1 and TNF synthesis from macrophages by up-regulating inhibitory NF-kB (in-hibitory NF-kB) synthesis in monocyte/macrophage cell lines. Inhibitory NF- kB prevents NF- kB from translocating to the nucleus where NF- kB functions as a transcriptional activator for the proinflammatory cytokines. IL-11 has also been shown to inhibit the synthesis of IFN-g and IL-2 by CD41 T cells. IL-11 functions as a Th2-type cytokine, with induction of IL-4 and Inhibition of Th1-type cytokines. IL-11 does not induce the synthesis of IL-10 or TGF- b. This indicates that IL-11 is a direct inhibitor of Th1 lymphocytes and does not act indirectly through induction of IL-10.
IL-13 and IL-4 share a common cellular receptor (IL-4 type 1 receptor), and this accounts for many of the similarities between these two anti-inflammatory cytokines. IL-4 and IL-13 share only 20% to 25% primary amino acid homology, but the majora-helical regions that are essential for their activity are highly homologous. IL-13 can down-regulate the production of TNF, IL-1, IL-8, and MIP-1α by monocytes and has profound effects on expression of surface molecules on both monocytes and macrophages.
Like many cytokines, TGF-β has both pro- and anti-inflammatory effects. It functions as a biological switch, antagonizing or modifying the action of other cytokines or growth factors. The presence of other cytokines may modulate the cellular response to TGF-β, and the effect may differ depending on the activation state of the cell. TGF-β is capable of converting an active site of inflammation into one dominated by resolution and repair. TGF-b often exhibits disparate effects with immune-enhancing activity in local tissues and immune-suppressive activity in the systemic circulation. TGF-β1 suppresses the proliferation and differentiation of T cells and B cells and limits IL-2, IFN- g, and TNF production. TGF-β1 acts as a monocyte/macrophage deactivator in a manner similar to IL-10. However, TGF-βis less potent an inhibitor than IL-10 and has little or no effect on IL-1 production. The severe and uncontrolled inflammatory reactions observed in the TGF-β1 knockout mouse attests to the physiologic role of TGF-b as an endogenous anti-inflammatory cytokine.
There are also many soluble cytokine receptors as anti-inflammatory molecules. Such as: type 1 (p55) and type 2 (p75) receptors for human TNF-α.