The process of inflammation is crucial in the body's fight against pathogenic invasion. Under certain circumstances however, inflammation can be lethal, for example following sepsis. Sepsis occurs in 1-2% of hospital admissions and is secondary to the appearance of bacterial toxins in the circulation. The frequent progression of sepsis to septic shock results in hypotension and inadequate tissue perfusion. Septic shock carries a 45% risk of mortality making it the most common causes of death in intensive care units. In addition to acute inflammation, chronic and inappropriate inflammation occurs as a central component of both allergy and autoimmune disease. Airway allergies such as asthma and rhinitis are particularly common affecting 50-60 million Americans. The American Autoimmune Related Disease Association lists over 50 different autoimmune diseases. Some of these are common such as multiple sclerosis, type 1 diabetes, Crohn's disease and rheumatoid arthritis, which in total affect 16-26 million people world-wide. Psoriasis represents a further common example of inflammatory disease affecting over 7 million people in the U.S. alone. The development of anti-inflammatories therefore represents a major priority for the pharmaceutical industry. One target that has received considerable attention is IL-10. The cytokine, which was first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Due to the promise associated with IL-10, a number of therapeutic candidates based on this cytokine are in development and clinical studies have demonstrated the benefit of recombinant IL-10 to both Crohn's disease and psoriasis patients. More recently a family of IL-10-related cytokines has emerged, comprising a series of herpesviral and poxviral members and several cellular sequence paralogs, including IL-19, IL-20, IL-22, IL-24 and IL-26. Although the predicted structure of these molecules is conserved, certain receptor-binding residues are variable and define the interaction with specific heterodimers of different type-2 cytokine receptors. This leads, through the activation of signal transducer and activator of transcription (STAT) factors, to diverse biological effects. For example, IL-22 mediates acute-phase response signals in hepatocytes and IL-20 induces the hyperproliferation of keratinocytes, which has been proposed as a pathogenic mechanism of psoriasis. Thus the therapeutic potential of IL-10 and other members of this family is far from being fully exploited and further development should hopefully result in the identification of new and improved candidates for a variety of serious, debilitating and unmet diseases.

Link to journal abstract:

Adapted from Fickenscher et al, Trends Immunol 2002 Feb;23(2):89-96

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