TNF, IL-1, and IL-6 produced during the innate immune response to infection or tissue damage have systemic effects that contribute to host defense and are responsible for many of the clinical manifestations of infection and inflammatory disease (see Fig. 1).

 • Fever. TNF and IL-1 act on the hypothalamus to induce an increase in body temperature (fever). These cytokines are therefore called endogenous pyrogens (i.e., host-derived fever-causing agents, to distinguish them from LPS, which was considered an exogenous [microbe-derived] pyrogen). This distinction is mainly of historical significance because we now know that even LPS induces fever by stimulating production of TNF and IL-1. These cytokines increase synthesis of prostaglandins in hypothalamic cells, and prostaglandins stimulate the production of neurotransmitters that reset the body’s steady-state temperature to a higher level by reducing heat loss (via vasoconstriction) and increasing heat generation (through effects on skeletal muscle and fat). Prostaglandin synthesis inhibitors, such as aspirin, reduce fever by blocking this action of the cytokines. The role of fever in host defense is not well understood but may relate to enhanced metabolic functions of immune cells, impaired metabolic functions of microbes, and changes in the behavior of the febrile host that reduces risk for worsening infections and injury.

• Leukocytosis. TNF, IL-1, and IL-6 produced at inflammatory sites circulate to the bone marrow and promote the release of neutrophils and monocytes, and other cytokines called colony-stimulating factors stimulate production of these cells, leading to elevated numbers of these white cells in the blood (leukocytosis). This enhances leukocyte migration into tissues, which can aid in antimicrobial defense but can also contribute to inflammatory damage to tissues.

• Acute-phase response. TNF, IL-1, and IL-6 induce hepatocytes to produce acute-phase proteins, including CRP, SAP, and fibrinogen, which are secreted into the blood. Elevated plasma CRP is used clinically as a sign of an inflammatory process. CRP and SAP play protective roles in infections, as we dis cussed earlier in the chapter, and fibrinogen, the precursor of fibrin, contributes to hemostasis and tissue repair.

Fig1. 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.

In severe infections, TNF may be produced in large amounts and causes systemic clinical and pathologic abnormalities. If the stimulus for cytokine production is sufficiently strong, large amounts of TNF may be made, enter the bloodstream, and act at distant sites (see Fig. 1). The principal pathologic actions of TNF are as follows:

• TNF inhibits myocardial contractility and vascular smooth muscle tone, and increases endothelial permeability, resulting in a marked decrease in blood pressure, or shock.

 • TNF causes intravascular thrombosis, mainly as a result of impairment of the normal anticoagulant properties of the endothelium. TNF stimulates endothelial cell expression of tissue factor, a potent activator of coagulation, and inhibits expression of thrombomodulin, an inhibitor of coagulation. The endothelial alterations are exacerbated by activation of neutrophils, leading to vascular plugging by these cells.

• Prolonged production of TNF causes wasting of muscle and fat cells, called cachexia. This wasting results from TNF induced appetite suppression and reduced synthesis of lipoprotein lipase, an enzyme needed to release fatty acids from circulating lipoproteins so they can be used by the tissues.

A systemic complication of severe infection, usually bacterial or fungal, is a syndrome called sepsis, clinically characterized by fever, fast heart and respiratory rates, metabolic abnormalities, and mental disturbances. Bacterial sepsis is most often initiated by LPS (also called endotoxin) released from gram negative bacteria or lipoteichoic acid released from gram-positive bacteria, which may enter the bloodstream and disseminate widely. TLR signaling is then induced in cells in many organs by these bacterial PAMPs, leading to the production of TNF and other cytokines, including IL-12, IFN-γ, IL-6, and IL-1. In the most severe form of sepsis, called septic shock, there is vascular collapse and disseminated intravascular coagulation, caused by the effects of high doses of TNF, discussed earlier. The level of serum TNF may be predictive of the outcome of severe sepsis. Septic shock can be reproduced in experimental animals by the administration of LPS, lipoteichoic acid, or TNF. Antagonists of TNF can prevent mortality in the experimental models, but clinical trials with anti-TNF antibodies or with soluble TNF receptors have not shown a benefit in patients with sepsis. The cause of this therapeutic failure is not known, but it may be because other cytokines elicit the same responses as TNF.

A syndrome similar to septic shock may occur as a complication of noninfectious disorders, such as severe burns, trauma, pancreatitis, and other serious conditions associated with inflammation. This has been called the systemic inflammatory response syndrome (SIRS).

Acute inflammation may cause tissue injury because the effector mechanisms that leukocytes use to kill microbes are also toxic to host tissues. The proteolytic enzymes, ROS and NO, produced by phagocytes that accumulate at a site of infection, can injure host cells and degrade extracellular matrix if they are generated in large quantities, especially if the microbes resist being killed and continue to stimulate innate immune responses. In fact, at least part of the pathology associated with infections is due to the inflammatory responses and not the direct toxic effects of the microbes. Acute inflammation also causes tissue damage in the setting of autoimmune diseases, in which case neutrophils and macrophages accumulate and become activated as a result of stimulation of the adaptive immune system by self antigens. As in inflammation induced by infections, TNF, IL-1, IL-6, and IL-12 are key inducers of inflammation in autoimmune diseases. Antagonists against all of these cytokines or their receptors are used clinically to reduce inflammation in patients with inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم رعاية الصحن الشريف ينشر لافتات الحزن بذكرى شهادة الإمام الجواد (عليه السلام)

قسم العلاقات العامة يقيم مجلس عزائه الأسبوعي لاستذكار فضائل أهل البيت (عليهم السلام)

متحف الكفيل يستعرض درعًا هنديًّا يعود إلى القرن التاسع عشر

ضمن محفلها الأسبوعيّ.. دار علوم نهج البلاغة تقدّم محاضرةً عن تحرير الإنسان من قيود المنصب

المزيد

الآخبار الصحية

طريقة مبتكرة للكشف المبكر عن أمراض القلب والشرايين

منظمة الصحة تحذر من خطر إدمان الشباب لأكياس النيكوتين

خبراء يحذرون من عادة شائعة تهدد صحة الملايين

خبير يكشف 5 حقائق طبية صادمة وغير معروفة

المزيد

الآخبار التكنلوجية

الأولى في العالم.. الصين تجري تجربة رائدة في الفضاء باستخدام "جنين اصطناعي"

دراسة حديثة تفند ربط التستوستيرون بالمخاطرة لدى الرجال

ميتا تضيف وضع "المحادثة المخفية" إلى تطبيق "واتساب"

فوبيا المرتفعات ليست من الدماغ.. دراسة تكشف السبب

المزيد

مواضيع ذات صلة

Stages of T-Cell Maturation

Mechanisms that Limit Innate Immune Responses

Stimulation of Adaptive Immunity

Immuno microscopy

V(D)J Recombination

Role of Macrophages in Tissue Repair

Ingestion and Killing of Microbes by Activated Phagocytes

Sequence of Events in Inflammation: Vascular Changes and Leukocyte Migration Into Tissues

Double Antibody Sandwich ELISA (DAS ELISA)

Enzyme Immunosorbent Assays

Antibody Structure and Function

Apoptosis in the Immune System