Tumor Necrosis Factor-α Signaling in Macrophages

Abstract

Tumor necrosis factor-α (TNFα) was cloned over 2 decades ago and its identification in part led to the discovery of a super family of tumor necrosis factors (TNFs) and their receptors. TNFα signals through two transmembrane receptors, TNFR1 and TNFR2, and regulates a number of critical cell functions including cell proliferation, survival, differentiation, and apoptosis. Macrophages are the major producers of TNFα and interestingly are also highly responsive to TNFα. Aberrant TNFα production and TNF receptor signaling have been associated with the pathogenesis of several diseases, including rheumatoid arthritis, Crohn’s disease, atherosclerosis, psoriasis, sepsis, diabetes, and obesity. TNFα has been shown to play a pivotal role in orchestrating the cytokine cascade in many inflammatory diseases and because of this role as a “master-regulator” of inflammatory cytokine production, it has been proposed as a therapeutic target for a number of diseases. Indeed anti-TNFα drugs are now licensed for treating certain inflammatory diseases including rheumatoid arthritis and inflammatory bowel disease. In this review we discuss the discovery of TNFα and its actions especially in regulating macrophage biology. Given its importance in several human diseases, we also briefly discuss the role of anti-TNFα therapeutics in the treatment of inflammatory diseases.

TNF-α Antibody Therapy in Combination With the T-Cell–Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddmRat

“…The proinflammatory cytokine TNF-a, expressed in the infiltrating immune cells, is known to be a key player in the pathology of many autoimmune diseases, including T1D (9,12,13). However, although a monotherapy with anti-TNF-a is an established successful therapy in a number of autoimmune diseases (15)(16)(17), anti-TNF-a is not effective in T1D treatment (18)(19)(20)(21)(22)(23).…”

“…Cumulative evidence from studies in a variety of other autoimmune diseases supports the contention that the inflammatory process in the affected organs always goes along with a high TNF-a expression (9)(10)(11)(12)(13). Anti-TNF-a therapy is therefore an established therapeutic principle (14)(15)(16) in rheumatoid arthritis, inflammatory bowel diseases, lupus erythematosus, Sjögren syndrome, psoriasis, and Hashimoto thyroiditis (10,15,17).…”

Immunological Profiles in HIV Positive Patients with or without Opportunistic Infections and the Influence of Highly Active Antiretroviral Therapy: A Systematic Review and Update

“…During HIV disease the cytokine is able to induce viral expression in severely infected cells [75]. Various studies document an initial burst of TNF-α levels during primary HIV infection [34], although much higher frequency and concentration is observed during progressive disease [42,76], that may be linked to continuous TNF-α activation.…”

TNF‑α and soluble forms of TNF receptors 1 and 2 in the serum of patients with Crohn’s disease and ulcerative colitis

“…A characteristic feature of CD is inflammation involving the entire intestinal wall, where various cytokines, such as tumor necrosis factor-α (TNF-α)play a key role. 4,6,7 TNF-α affects the cellular signaling pathways through 2 receptors: 55 KDa TNF receptor 1 (TNFR1), also known as p55, and 75 KDa TNF receptor 2 (TNFR2), also known as p75. [6][7][8] These are type I cysteine-rich membrane proteins, which differ in structure, ligand affinity, distribution, and function.…”

“…As a result of proteolytic detachment of the receptor extracellular domain by TNF-α-converting enzyme, the so called soluble forms of TNF receptors (sTNFR1 and sTNFR2) are formed. 6,9 Soluble receptor forms have been detected in the cerebrospinal and intraarticular fluid, peritoneal fluid, urine, and serum.…”