Cytokine inhibitors

Cytokine inhibitors are used to describing a heterogeneous group of drugs which 1) decrease the synthesis of cytokines; 2) decrease their concentration in free active form: 3) block their interaction with specific receptors, or 4) interfere with the signaling of cytokine receptors.

Cytokine Inhibitors: Inhibiting of Cytokine Synthesis

1) Reduction of the number of cytokine producing cells

All drugs which decrease the number of producing cells implicitly also inhibit cytokine synthesis. Examples of the cytokine inhibitors are general cytostatic drugs, some of which—such as azathioprine or methotrexate—are approved as immunosuppressants or antiinflammatory agents. A cytostatic drug with a higher selectivity for immune cells is mycophenolate. Antibodies directed against structures of T lymphocytes, as the monoclonal antibody against parts of the antigen receptor of T lymphocytes, muromonab CD3, decreases selectively the circulating pool of this lymphocyte subpopulation—predominantly by complement lysis—and in this manner is immunosuppressive, acting as cytokine inhibitors.

2) Without affecting viability of cells

Cytokine synthesis can be inhibited without affecting viability of cells. Such a mode of action is exerted by the glucocorticoids (e.g. prednisone), the anti-inflammatory or immunosuppressive effects of which were in clinical use long before it became known cytokine inhibitors. Such as inhibiting interleukin-1, tumor necrosis factor or interleukin-2, is the major mechanism of their action. Glucocorticoids bind to the glucocorticoid receptor in the cytoplasm of cells, releasing it from binding to the heat shock protein HSP 90. The receptor then translocates to the nucleus and binds to a "glucocorticoid responsive element" (GRE) that is present in the promoter of more than 100 genes. It inhibits cytokine gene expression by several mechanisms.
* The GRE interacts negatively with other promoter elements implicated in its activation such as the NFκB site.
* The bound glucocorticoid receptor protein negatively interacts with transcription factors (e.g. NFκB).
* Proteins are induced, which interfere with signaling pathways such as the inhibitor of NFκB, IκB.
* The glucocorticoid receptor in its ligated form directly binds to signaling elements of receptors which induce cytokine synthesis (e.g. NFκB or the p38 kinase) and blocks their action.

Cytokine Inhibitors: Inhibiting Cytokines in Free Active Form

1) Monoclonal antibody against cytokines

A very specific way, in principle, to block cytokines is to generate monoclonal antibodies which combine with the cytokine and thus prevent it from binding to its receptor. Although this has been probed for many different cytokines only one cytokine inhibitor so far has proven to be of sufficient clinical value—infliximab, which is a humanized monoclonal antibody directed against tumor necrosis factor. This monoclonal antibody originally was raised in mice; the antigen-binding parts then were exchanged by gene technology in a human immunoglobulin IgG molecule ("humanized") which drastically increases the half-life in human beings and decreases the chance of eliciting antibodies (to mouse protein!) which limit the activity.

2) Soluble receptors

Cytokines exert their biological activities by binding to membrane receptors of target cells. As a physiological regulatory mechanism the extracellular—cytokine binding—parts can be released, which curtails the biological action of the respective cytokine. This principle of "soluble receptors" has been successfully exploited. To enhance effectiveness and half-life in vivo, soluble receptors were transferred (by gene technology) to non-antigen-binding parts of the IgG molecule. Such a construct of cytokine inhibitor is etanercept containing the soluble receptor for tumor necrosis factor.

Cytokine Inhibitors: Inhibiting Cytokine Receptors

Similar to inhibiting cytokines, monoclonal antibodies can also be effective against their receptors thus preventing the function of the cytokine in question. Basiliximab and daclizumab are representing this kind of cytokine inhibitors. They are humanized monoclonal antibodies against the interleukin-2 receptor. By blocking the receptor for this central T lymphocyte growth factor they suppress cellular immune reactions. Interleukin-1 (together with tumor necrosis factor) is a very efficacious proinflammatory cytokine. Provided it is singular, nature has created an antagonist which when secreted dampens the action of interleukin-1. Anakinra represents this antagonist which is produced by gene technology and displays anti-inflammatory properties.
With the potential of modern molecular biological methods, cytokines (being proteins) can be modified with the aim to change their biological properties. Thus a mutated protein (mutein) of interleukin-4 has been generated which behaves as an IL-4 receptor antagonist (and also as an IL-13 receptor antagonist as both two chain receptors share one common receptor chain). This mutein is at present tested in clinical studies for its effectiveness to treat allergic diseases (predominantly asthma). Similarly, chemokines mutated to chemokine receptor antagonists are evaluated in human immunodeficiency virus (HIV) infections as this virus uses some chemokine receptors such as CxCR5, or CCR3, and CCR5 as co-receptors for its entry into cells.

Cytokine Inhibitors: Inhibiting Cytokine Receptor-Dependent Signaling

After the binding of a cytokine to its receptors the biological response is transduced by metabolic signals, generally involving multiple signaling cascades. Sirolimus (rapamycin), a representative of this kind of cytokine receptors, by selectively inhibiting the protein kinase mTOR (target of rapamycin) is an effective immunosuppressive drug as mTOR is an essential component of the signaling of the receptor for interleukin-2. mTOR plays a central role in several biological processes, including cell cycle control, and thus its inhibition prevents proliferation of activated T lymphocytes.

Cytokine Inhibitors References

• Cytokine inhibitors[M]. CRC Press, 2000.