Tumor necrosis factor-alpha related signal pathways and neuronal diseases

Yuki Murakami, Yukio Imamura, Satoko Mitani, Masato Hoshi, Yuko Arioka, Yasuko Yamamoto, Akitoshi Seiyama, Kuniaki Saito

Research output: Chapter in Book/Report/Conference proceedingChapter


Tumor necrosis factor-alpha (TNF-α) is a potent pro-inflammatory cytokine exerting pleiotropic effects on various cell types and plays a critical role in the pathogenesis of chronic inflammatory diseases. TNFis a type II transmembrane glycoprotein, containing a C terminus that is external to the cell and a cytoplasmic domain. It can theoretically act in two states, as membrane bound or as a soluble form. A precursor of the soluble form of TNF-α(sTNF-α) transmembrane TNF-α(tmTNF-α) is expressed on activated macrophages and lymphocytes as well as other cell types. The sTNF- can be cleaved from the membrane with a proteolysis by the metalloprotease/disintegrin/cysteine-rich family called TNF-α-converting enzyme (TACE). The sTNF- mediates its biological activities through binding to types 1 and 2 TNF receptors (TNFR1/2) of remote tissues. The structure of TNF- is described as ' β-jellyroll' in which eight antiparallel β-strands form a sandwich 3D structure. In mammals, the TNF-αgene is located in tandem within the MHC locus and it contains four exons and three introns. Recent studies suggest that not only sTNF-α, but also tmTNF-α is involved in the inflammatory response. TNF-α is primarily expressed by activated immune cells such as macrophages, monocytes, neutrophils, NK-cells, and T-cells. TNFexpression has been detected in a number of transformed cell lines including astrocytes, microglia, smooth muscle cells, and fibroblast. When TNF-α is induced locally and in a controlled way, it provides many useful signals leading to resolution of infection and initiation of tissue repair. But defective regulation or chronic and excessive production of TNF-α can lead to autoimmune diseases such as rheumatoid arthritis (RA) and Crohn's disease. While it is clear that the TNF-α signaling pathway is an appropriate therapeutic target for the treatment of autoimmune diseases, total inhibition of TNF-α leads to some serious side effects, such as decreased immune functioning, onset of autoimmune diseases and increased risk of malignancy. In this chapter, TNF-α is discussed from molecular mechanism to future therapeutic potential for the patho-physiology, respectively, in the following section: (1) structure and enzyme regulation, (2) signal pathway, (3) therapeutic strategies in the future studies.

Original languageEnglish
Title of host publicationTumor Necrosis Factor
Subtitle of host publicationStructure, Enzyme Regulation and Role in Health and Disease
PublisherNova Science Publishers, Inc.
Number of pages28
ISBN (Print)9781624177217
Publication statusPublished - 01-12-2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)


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