Natural Inhibitors of Tumour Necrosis Factor-α Production, Secretion and Function

Abstract

Tumour necrosis factor-a a (TNF), originally discovered by its antitumor activity, is one of the most pleotropic cytokines acting as a host defence factor in immunologic and inflammatory responses. Although the antitumour activity and mediation of inflammation by TNF could be beneficial to the host, unregulated TNF is now known to be the basis for development of various diseases including septic shock, the wasting disease, cachexia, and various inflammatory and/or autoimmune diseases. With an attempt to find potential therapeutic agents for TNF-mediated diseases, research during the last decade has led in the identification of well over one hundred natural inhibitors of either TNF production/secretion or function. This review summarises the structures, mechanism of action and therapeutic potential of these natural products.Key words: TNF, natural inhibitors, adhesion molecules, NF-k kB, cAMP, inflammation, cytotoxicity. IntroductionTumour necrosis factor-a (TNF; also known as cachectin) was originally discovered by its antitumour activity, but it is now recognised to be one of the most pleotropic cytokines acting as a host defence factor in immunologic and inflammatory responses (1), (2). Among its many different activities, TNF has effects on the vascular endothelium which leads to upregulation of various cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and endothelial-leucocyte adhesion molecule-1 (ELAM-1) (3). The regulated expression of these adhesion molecules and their counter-receptors on leucocytes mediates the adhesion and extravasation of white blood cells during inflammatory reaction. While mediation of inflammation and anti-tumour activity by TNF could be beneficial to the host, overproduction of TNF is the basis for the development of various diseases. There is now overwhelming evidence to suggest that TNF mediates the wasting disease, cachexia, associated with chronic diseases such as cancer and AIDS (4), (5). TNF also plays pivotal roles in the development of pathologies such as disseminated intravascular coagulation and death in septic shock and cerebral malaria (6), (7) and a range of inflammatory diseases including asthma (8) and dermatitis, multiple sclerosis, inflammatory bowel disease, cystic fibrosis, rheumatoid arthritis, multiple sclerosis and immunological diseases (9). It is thus clear that suppression of TNF production/release or inhibition of its function could benefit in the treatment of these TNF-mediated diseases. Potential Targets for Natural ProductsThe various target sites for modulation of TNF production and function by antibodies and pharmacological agents have been reviewed recently (9), (10). Potential target sites for inhibitory small molecular weight natural products could be broadly divided into three areas: i) inhibition of TNF production and secretion, ii) TNF receptor antagonism, and iii) inhibition of TNF function through modulation of its signal transduction pathway(s). During the 1990©s,...

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