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0031-6997/03/5502-241-269$7.00
Pharmacol Rev 55:241-269, 2003

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Interleukin-10 Therapy—Review of a New Approach

K. Asadullah, W. Sterry and H. D. Volk

Corporate Research Business Area Dermatology (K.A.), Schering AG, Berlin, Germany; and Departments of Dermatology and Allergology (W.S.) and Institute of Medical Immunology (H.D.V.), University Hospital Charité, Humboldt University, Berlin, Germany

Abstract
I. Introduction
II. Interleukin-10
    A. Interleukin-10 and Interleukin-10 Homologs
    B. Interleukin-10 Promoter and Interleukin-10 Polymorphisms
    C. Regulation of Interleukin-10 Secretion
III. Interleukin-10 Receptors and Signaling
    A. Interleukin-10 Receptors and Other Cytokine Receptor Family Type 2 Members
    B. Interleukin-10 Receptor Polymorphisms
    C. Interleukin-10 Receptor Signaling
IV. Immunobiology of Interleukin-10
    A. Effects of Interleukin-10 on Immune Cells in Vitro
        1. Effects on Myeloid Antigen-Presenting Cells.
        2. Effects on T Cells.
        3. Effects on Natural Killer Cells.
        4. Effects on Other Immune Cells.
        5. Effects on Epithelial Cells.
    B. Effects of Interleukin-10 in Animals/Animal Models
        1. Interleukin-10 Knockout Mice.
        2. Inflammation and Autoimmune Models.
        3. Tumor Models.
        4. Experimental Models of Infections.
    C. Interleukin-10 and Interleukin-10 Receptor Expression in Diseases
        1. Expression in Malignant Diseases.
            a. Melanoma.
            b. Carcinoma.
            c. Lymphoma.
            d. Prognostic Value of Interleukin-10 Overexpression.
        2. Autoimmune and Inflammatory Diseases.
            a. Systemic Lupus Erythematosus.
            b. Systemic Sclerosis.
            c. Bullous Pemphigoid.
            d. Psoriasis.
            e. Rheumatoid Arthritis.
            f. Allergic Contact Dermatitis and Other Non-Atopic Eczemas.
            g. Chronic Inflammatory Bowel Diseases.
            h. Multiple Sclerosis.
            i. Transplantation.
        3. Expression in Atopic Disorders.
            a. Atopic Dermatitis.
            b. Allergic Asthma.
        4. Expression in Infection.
    D. Interleukin-10 and Interleukin-10 Receptor Polymorphisms and Diseases
V. Interleukin-10 As a Therapeutic Agent
    A. Phase I Trials in Healthy Volunteers
    B. Prevention of Cytokine Release in Transplant Patients and Jarisch-Herxheimer Reaction
    C. Therapy of Crohn's Disease
    D. Therapy of Rheumatoid Arthritis
    E. Therapy of Psoriasis
    F. Therapy of Viral Infections—Chronic Hepatitis C and Human Immunodeficiency Virus
VI. Prospects of Interleukin-10/Interleukin-10 Receptor As a Therapeutic Target
VII. Conclusions
Interleukin (IL)-10 is an important immunoregulatory cytokine produced by many cell populations. Its main biological function seems to be the limitation and termination of inflammatory responses and the regulation of differentiation and proliferation of several immune cells such as T cells, B cells, natural killer cells, antigen-presenting cells, mast cells, and granulocytes. However, very recent data suggest IL-10 also mediates immunostimulatory properties that help to eliminate infectious and noninfectious particles with limited inflammation. Numerous investigations, including expression analyses in patients, in vitro and animal experiments suggest a major impact of IL-10 in inflammatory, malignant, and autoimmune diseases. So IL-10 overexpression was found in certain tumors as melanoma and several lymphomas and is considered to promote further tumor development. Systemic IL-10 release is a powerful tool of the central nervous system to prevent hyperinflammatory processes by activation of the neuro-endocrine axis following acute stress reactions. In contrast, a relative IL-10 deficiency has been observed and is regarded to be of pathophysiological relevance in certain inflammatory disorders characterized by a type 1 cytokine pattern such as psoriasis. Recombinant human IL-10 has been produced and is currently being tested in clinical trials. This includes rheumatoid arthritis, inflammatory bowel disease, psoriasis, organ transplantation, and chronic hepatitis C. The results are heterogeneous. They give new insight into the immunobiology of IL-10 and suggest that the IL-10/IL-10 receptor system may become a new therapeutic target.

Address correspondence to: Dr. Khusru Asadullah, Head of Corporate Research Business Area Dermatology, Schering AG, D-13342 Berlin, Germany. E-mail: khusru.asadullah{at}schering.de




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