One of the earliest responses of the innate immune system to infection and tissue damage is the secretion of cytokines by tis sue cells, which is critical for the acute inflammatory response. The cytokines of innate immunity have some important general properties and functions (Table 1):

• They are produced mainly by tissue macrophages and DCs, although other cell types, including mast cells, some fibroblasts, endothelial cells, and epithelial cells, can also produce them.

• Most of these cytokines act on cells close to their cell of origin (paracrine action). In some severe infections, enough of the cytokines may be produced so that significant amounts enter the circulation and act at a distance (endocrine action).

 • Different cytokines may share similar actions but some actions may be unique to one cytokine. One cytokine may stimulate the production of others, thus setting up cascades that amplify the reaction or induce new reactions.

• The cytokines of innate immunity serve several roles: inducing inflammation, inhibiting viral replication, promoting T-cell responses, and regulating innate immune responses. These functions are described next and later in the chapter.

• Many cytokines that are produced by innate immune cells, such as TNF, IL-17, IL-5, and IFN-γ, are also produced by T lymphocytes in adaptive immune responses.

 • Three of the most important proinflammatory cytokines of the innate immune system are TNF, IL-1 (both of which we have mentioned several times), and IL-6. We will discuss the major features of these cytokines, focusing mainly on TNF and IL-1, before describing their role in acute inflammation.

Table1. Cytokines of Innate Immunity

Tumor Necrosis Factor

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 lymphotoxin. 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.

Interleukin-1

 IL-1 is also a mediator of the acute inflammatory response and has many actions similar to those of TNF. A major cellular source of IL-1, like that of TNF, is activated mononuclear phagocytes. IL-1 is also produced by many cell types other than macrophages, such as neutrophils, DCs, epithelial cells (e.g., keratinocytes), and endothelial cells. There are two forms of IL-1, called IL-1α and IL-1β, which are less than 30% homologous, but they bind to the same cell surface receptors and have the same biologic activities. The main biologically active secreted form in the setting of infections and most immune responses is IL-1β.

IL-1 production usually requires two distinct signals: one that activates new gene transcription and production of a 33-kD precursor pro–IL-1β polypeptide and a second that activates the inflammasome to proteolytically cleave the pre cursor to generate the 17-kD mature IL-1β protein. As discussed earlier in this chapter, IL-1β gene transcription is induced by TLR, NLR, and RLR signaling pathways that activate NF-κB, whereas pro–IL-1β cleavage is mediated by caspase-1, which is activated by inflammasomes. TNF can also stimulate phagocytes and other cell types to produce IL-1. This is an example of a cascade of cytokines that have simi lar biologic activities. Unlike most secreted proteins, neither IL-1α nor IL-1β has a hydrophobic signal sequence to target the nascent polypeptide to the endoplasmic reticulum mem brane. As discussed earlier, IL-1β may be secreted through membrane pores formed by gasdermin D and/or released from cells dying by pyroptosis.

IL-1 mediates its biologic effects through a membrane receptor called the type I IL-1 receptor, which is expressed on many cell types, including endothelial cells, epithelial cells, and leukocytes. This receptor is an integral membrane protein that contains an extracellular ligand-binding Ig domain and a TIR signaling domain in the cytosolic region, which we described earlier in reference to TLRs. The signaling events that occur when IL-1 binds to the type I IL-1 receptor are similar to those triggered by TLRs and result in the activation of NF-κB and AP-1 transcription fac tors. A second IL-1 receptor, called the type II IL-1 receptor, appears incapable of activating downstream signals, and serves as a decoy receptor that limits responses to IL-1.

Interleukin-6

IL-6 is another important cytokine in acute inflammatory responses that has both local and systemic effects. It induces the synthesis of acute-phase reactants by the liver and promotes the differentiation of IL-17–producing helper T cells. IL-6 is synthesized by mononuclear phagocytes, DCs, vascular endothelial cells, fibroblasts, and other cells in response to PAMPs and DAMPs and in response to IL-1 and TNF. IL-6 is a homodimer that belongs to the type I cytokine family. The receptor for IL-6 consists of a cytokine-binding polypeptide chain and a signal-transducing subunit (called gp130) that is also the signaling component of receptors for other cytokines. The gp130 subunit is expressed on many cell types, but the IL-6 binding chain is expressed only by leukocytes and hepatocytes, as a transmembrane protein in association with gp130. A soluble form of the IL-6 binding chain is generated by proteolytic cleavage of the membrane form and is present in blood and tissue fluids. This soluble form can bind IL-6, and then the complex can associate with the extracellular part of gp130 on many cell types and initiate signaling. This mechanism is called trans-signaling. The IL-6 receptor engages a signaling pathway that activates the transcription factor STAT3. IL-6 is a major contributor to inflammation in several human inflammatory diseases, including rheumatoid arthritis, and antibodies specific for the IL-6 receptor are used to treat some forms of arthritis. Some lymphoproliferative disorders, such as Castleman disease, are caused by human herpesvirus–8 (HHV 8), a virus that encodes a homolog of IL-6, and IL-6 blockade has been used to treat these diseases.

Other Cytokines Produced During Innate Immune Responses

In addition to TNF, IL-1, and IL-6, DCs and macrophages activated by PAMPs and DAMPs produce other cytokines that have important roles in innate immune responses (see Table 1). We will discuss the main features of some of these cytokines and their roles in innate immunity in this section; interferons and inhibitory cytokines are discussed later in the chapter.

IL-12 is secreted by DCs and macrophages and has several inflammatory actions: it stimulates IFN-γ production by ILC1s, NK cells, and T cells; enhances NK cell–and CTL mediated cytotoxicity; and promotes differentiation of Th1 cells. IL-12 exists as a disulfide-linked heterodimer of 35-kD (p35) and 40-kD (p40) subunits. The p35 subunit is a member of the type I cytokine family, and the p40 subunit is also a component of the cytokine IL-23, which is involved in the differentiation of Th17 cells. Therefore, an antibody specific for p40 blocks both IL-12 and IL-23 and thus inhibits the IL-12 dependent development of Th1 cells and the IL-23–dependent development of Th17 cells. This antibody is approved for the treatment of inflammatory bowel disease and psoriasis, which are caused by Th1 and/or Th17 cytokines.

The principal sources of IL-12 are activated DCs and macrophages. Many cells appear to synthesize the p35 subunit, but macrophages and DCs are the main cell types that produce the p40 component and therefore the biologically active cytokine. During innate immune reactions to microbes, IL-12 is produced in response to TLR and other pattern recognition receptor signaling induced by many microbial stimuli, including bacterial LPS or lipoteichoic acid and viral nucleic acids. IFN-γ produced by NK cells or T cells also stimulates IL-12 production, contributing to a positive feedback loop.

The receptor for IL-12 is a heterodimer composed of β1 and β2 subunits, both of which are members of the type I cytokine receptor family. Both chains are required for high-affinity binding of IL-12 and for signaling, which activates the transcription factor STAT4. Expression of the β2 chain of the IL-12 receptor is itself enhanced by IFN-γ, whose production is stimulated by IL-12. This is an example of a positive amplification loop in immune responses. Studies with gene knockout mice and the phenotype of rare patients with mutations in the IL-12 receptor support the conclusion that IL-12 is important for IFN-γ production by NK cells and T cells and for host resistance to intracellular bacteria and some viruses. For example, patients with mutations in the IL-12 receptor β1 subunit are highly susceptible to infections with intracellular bacteria, notably Salmonella and mycobacteria. IL-12 secreted by DCs during antigen presentation to naive CD4+ T cells promotes the differentiation of these cells into the Th1 subset of helper T cells, which are important for defense against intracellular infections. This is a key way in which innate immunity shapes adaptive immune responses.

IL-18 enhances the functions of NK cells, similar to IL-12. Recall that the production of biologically active IL-18, like that of IL-1, is dependent on inflammasomes. Also, like IL-1, IL-18 binds to a receptor that signals through a TIR domain. Children with gain-of-function mutations in NLRC4 have very high levels of inflammasome-generated IL-18 produced by intestinal epithelial cells and suffer from hemophagocytic lymphohistiocytosis, a systemic macrophage activation syndrome with several causes, but in this case likely due to excessive IL-18–driven production of IFN-γ from NK cells.

IL-15 stimulates the growth and functions of ILC1s, NK cells, and some T cells. IL-15 is structurally homologous to the T-cell growth factor IL-2, and the heterotrimeric IL-15 receptor shares two subunits with the IL-2 receptor. An interesting feature of IL-15 is that it can be expressed on the cell surface bound to the α chain of its receptor and in this form can be presented to and stimulate nearby cells that express a receptor composed of the other two chains (β and γ). IL-15 presented in this way by DCs to NK cells activates signaling pathways that promote NK cell IFN-γ production. IL-15 also serves as a survival factor for NK and memory CD8+ T cells.

IL-25, thymic stromal lymphopoietin (TSLP), and IL-33 are structurally unrelated cytokines produced by epithelial barrier cells, as well as other cell types, which stimulate ILC2s, Th2 cells, and mast cells to produce IL-4, IL-5, and IL-13. The latter cytokines are important for defense against helminths, but also contribute to allergic disease. IL-33 is constitutively expressed by barrier epithelial cells and stored in their nuclei. It is often called an alarmin because it is rapidly released from damaged epithelial cells and then stimulates innate and adaptive responses.

In addition to the cytokines discussed here, other cytokines play important roles in both innate and adaptive immune responses, including IL-2, IL-5, IL-17, and IFN-γ. These cytokines will be discussed in detail in Chapters 9 and 10, when we consider helper T-cell subsets that produce them.

اخر الاخبار

اخبار العتبة العباسية المقدسة

العتبة العباسية المقدسة تباشر تنفيذ المرحلة الثالثة من أعمال التوسعة

بمحافظة ذي قار.. قسم الشؤون الفكرية يقيم ندوة معرفية عن دور بصيرة العلماء في سلامة المجتمع

لأكثر من 180 طالبة.. مركز الثقافة الأسرية ينظم برنامج ربيع الثقافة المعرفي في بغداد

بحضور متوليها الشرعي.. العتبة العباسية المقدسة تطلق المرحلة الثالثة من القرعة العلنية لتوزيع قطع أراضي مدينة القمر السكنية لمنتسبيها

المزيد

الآخبار الصحية

سرّ بسيط لصحة القلب.. أطعمة تخفض الكوليسترول خلال أسابيع

سبب خفي لإعتام عدسة العين ؟

عوامل خفية تسرّع شيخوخة الدماغ

أسباب الرغبة الشديدة في تناول الحلويات والأطعمة النشوية

المزيد

الآخبار التكنلوجية

كندا تصنع كاسحة جليد من جيل جديد

رواد "أرتيميس 2" يكشفون تفاصيل حياتهم في الفضاء

حفريات صينية تكشف كائنات بحرية عاشت قبل 546 مليون عام

روسيا تطلق صاروخ "سويوز-2.1 إيه" من قاعدة بليسيتسك الفضائية

المزيد

مواضيع ذات صلة

Migration of Naive T Cells Into Lymph Nodes

Migration of Neutrophils and Monocytes to Sites of Infection or Tissue Injury

Leukocyte-Endothelial Interactions and Leukocyte Recruitment into Tissues

Formation of Pus

Feedback Control of the Macrophage and Neutrophil Responses

Macrophage and Neutrophil Responses During Inflammation

Natural Killer Cells

Integrins and Integrin Ligands

Selectins and Selectin Ligands

Anatomy and Functions of Lymphoid Tissues : Spleen

Eosinophils

Phagocytosis