Tumor necrosis factor (TNF) is a mediator of the acute inflammatory response to bacteria and other infectious microbes. The name of this cytokine derives from its original identification as a serum substance (factor) that caused necrosis of tumors, now known to be the result of inflammation and thrombosis of tumor blood vessels. TNF is also called TNF-α to distinguish it from the closely related TNF-β, which is also called lympho toxin. In innate immune responses, TNF is produced mainly by macrophages, and also by other cell types, including DCs, mast cells, and ILCs. In macrophages, it is synthesized as a homotrimeric nonglycosylated type II membrane protein that is able to bind to one form of TNF receptor. The membrane form of TNF is cleaved by a membrane-associated metalloproteinase, releasing a polypeptide fragment, and three of these polypeptide chains polymerize to form a triangular pyramid-shaped circulating TNF protein (Fig. 1). The receptor-binding sites are at the base of the pyramid, allowing simultaneous binding of the cytokine to three receptor molecules. TNF is a member of a large family of homologous proteins called the TNF superfamily, all of which share the feature of forming homotrimers.

Fig1. Structure of the TNF receptor with bound TNF. The ribbon structure depicts a top view (A) and a side view (B) of a complex of three type II TNF receptors (TNFR II) and one molecule of bound trimeric TNF, revealed by x-ray crystallography. The three TNFR II molecules, colored blue, together bind one homotrimer of TNF, colored green, with each receptor molecule interacting with two different TNF monomers in the homotrimer complex. The binding regions of one of the three TNFR II molecules to two TNF monomers are highlighted in the side view by orange ovals. Modified from Mukai Y, Nakamura T, Yoshikawa M, et al. Solution of the structure of the TNF-TNFR2 complex. Sci Signal. 2010;3:ra83.

There are two distinct TNF receptors called type I (TNFRI) and type II (TNFRII). The affinities of TNF for its receptors are unusually low for a cytokine, the Kd being only approximately 1 × 10⁻⁹ M for binding to TNFRI and approximately 5 × 10⁻¹⁰ M for binding to TNFRII. Both TNF receptors are present on most cell types. The TNF receptors are members of a large family of proteins called the TNF receptor superfamily, many of which are involved in immune and inflammatory responses. These receptors exist as trimers in the plasma membrane. Ligand binding to some TNF receptor family members, such as TNFRI, TNFRII, and CD40, leads to the recruitment of proteins called TNF receptor–associated factors (TRAFs) to the cytoplasmic domains of the receptors. The TRAFs activate transcription fac tors, notably NF-κB and AP1. Cytokine binding to some family members, such as TNFRI, may lead to recruitment of an adaptor protein that activates caspases and triggers apoptosis. Thus, different members of the TNF receptor family can induce gene expression or cell death, and some can do both.

TNF production by macrophages is stimulated by recognition of PAMPs and DAMPs. TLRs, NLRs, RLRs, and CDSs can all induce TNF gene expression, in part by activation of the NF-κB transcription factor. Many different microbial products can therefore induce TNF production. TNF has multiple local and systemic effects that account for many of the reactions in inflammation (Fig. 2). TNF is a major contributor to inflammation in several chronic inflammatory diseases, and TNF antagonists have become the mainstay of treatment of many of these diseases. Large amounts of this cytokine may be produced during infections with gram-negative and gram-positive bacteria, which express and release the cell wall components LPS and lipoteichoic acid, respectively. LPS binds to TLR4 and lipotechoic acid binds to TLR2. Septic shock, a life-threatening condition resulting from severe infections, is mediated in large part by TNF. We will discuss septic shock later in this chapter.

Fig2. Local and systemic actions of cytokines in inflammation. TNF, interleukin-1 (IL-1), and IL-6 have multiple local and systemic inflammatory effects. TNF and IL-1 act on leukocytes and endothelium to induce acute inflammation, and both cytokines induce the expression of IL-6 from leukocytes and other cell types. TNF, IL-1, and IL-6 mediate protective systemic effects of inflammation, including induction of fever, acute phase protein synthesis by the liver, and increased production of leukocytes by the bone marrow. Systemic TNF can cause the pathologic abnormalities that lead to septic shock, including decreased cardiac function, thrombosis, capillary leak, and metabolic abnormalities due to insulin resistance.

اخر الاخبار

اخبار العتبة العباسية المقدسة

في ذكرى تأسيسه.. متحف الكفيل يستعرض مسيرته في حفظ التراث الإنساني والإسلامي

قسم الشؤون الفكرية وجامعة ميسان يبحثان تعزيز التعاون العلمي المشترك

قسم الآليات يوضح عمل شعبة السيطرة في خدمة الزائرين ودعم أقسام العتبة العباسية المقدسة

متحف الكفيل يعرض درهمًا فضيًّا يوثّق مرحلة ولاية العهد للإمام الرضا (عليه السلام)

المزيد

الآخبار الصحية

السجائر الإلكترونية والإقلاع عن التدخين.. نتائج متباينة تثير الجدل العلمي

مصر تحقق إنجازاً دولياً جديداً في منظمة الصحة العالمية

دراسة: السباحة فعّالة أكثر من الجري في الحفاظ على صحة القلب

عامل خطر في بداية الحمل يؤخر تطور الكلام والمهارات الحركية لدى الرضع

المزيد

الآخبار التكنلوجية

أحلامك ليست عشوائية.. إليك ما يفعله دماغك أثناء نومك

روسيا.. العلماء يضاعفون الاستقرار الحراري للألواح الشمسية ثلاث مرات

علماء يكشفون سر سرعة الدلافين في السباحة

سلمي أو دموي.. هكذا تنتقل السلطة في مجتمع الجرذان

المزيد

مواضيع ذات صلة

Apoptosis in the Immune System

The Major Proinflammatory Cytokines of Innate Immunity: Interleukin-6

The Major Proinflammatory Cytokines of Innate Immunity: Interleukin-1

The Immune Receptor Family

Collectins and Ficolins

Soluble Effector Molecules of Innate Immunity: Pentraxins

Soluble Effector Molecules of Innate Immunity : The Complement System

MHC Genes

Cytokine-Producing Innate Lymphoid Cells

Epithelial Barriers

C-Type Lectins: Receptors for Microbial Carbohydrates

Antigen Capture and the Functions of Antigen-Presenting Cells