Shedding of extracellular domains of the two TNFα receptors by metalloproteinases can further alter

the biologic activity of TNFα by decreasing the number of cell signaling sites on target tissues and

increasing the amount of circulating inhibitors. Unlike other members of the TNF family that are

primarily involved in regulation of cell proliferation, TNFα has both proinflammatory and apoptosisinducing properties.95,104

Figure 7-6. TNF receptor signaling pathway. (Redrawn from Abbas AK, Lichtman AH. Cellular and Molecular Immunology. 5th ed.

Philadelphia, PA: Saunders; 2003.)

The principal function of TNFα is to recruit neutrophils and monocytes to foci of infections and to

activate these cells to eradicate microbes. TNFα activates the endothelium to upregulate the expression

of the adhesion molecules E- and P-selectin, ICAM-1, PECAM-1, and VCAM-1. It potently stimulates

these cells and macrophages to secret chemokines (IL-8, MIP-1α, and Gro-α) that enhance the affinity of

leukocyte integrins for their ligands and induce leukocyte chemotaxis and recruitment.105 TNFα also can

induce HMGB1 release by activated macrophages, which generates a forward feedback mechanism, as

HMGB1, by signaling through RAGE (see below), also induces TNFα release.106,107 TNFα by stimulating

the release of tissue factor, PAF, von Willebrand factor, and thromboplastin generates a state of

hypercoagulability. By inhibiting tissue-type plasminogen activator and thrombomodulin, it suppresses

fibrinolysis, decreases protein C and S activation, and increases thrombin formation. However, TNFα

also induces the release of a variety of anticoagulants (prostacyclin), fibrinolytics (urokinase-type

plasminogen activator), and vasodilators (NO, PGE2

), which may offset or balance the tendency toward

procoagulation. Most likely, the ultimate effect of TNFα depends on the location and quantity in which

it is produced and the vascular bed with which it interacts.4,95

3 Though clearly vital for host defense and microbial elimination, in severe infections, exuberant

production and aberrant release of TNFα wherein it possess endocrine function and can cause a plethora

of pathological sequelae. These systemic effects include fever by stimulating the production of PGE2 by

the hypothalamus (hence the name endogenous pyrogen), acute-phase protein production by the liver,

cachexia, inhibition of myocardial contractility and vascular tonus, and intravascular thrombosis due to

loss of normal anticoagulant properties of the endothelium and the production of tissue factor. TNFα is

central to the pathogenesis of systemic inflammatory response syndrome (SIRS) and septic shock, and

either state can be reproduced by the exogenous administration of TNFα.108,109 The organ dysfunction

characteristic of these states may result from the hypercoagulability and subsequent tissue ischemia

induced by this cytokine. Antagonists of TNFα can prevent mortality in experimental models, but

clinical trials with anti-TNFα antibodies or with soluble TNFα receptors have been to no avail.4,108 That

being said, anti-TNFα therapy has been pivotal in treating the more chronic diseases of rheumatoid

arthritis, psoriasis, and Crohn’s disease.

Soluble TNF receptors formed by proteolytic processing of both types of receptors bind and neutralize

TNFα and serve as an endogenous regulator of cytokine activity.39 TNFα also directly induces the

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expression and release of TNFα inhibitors, including IL-10, corticosteroids, and prostanoids, which in a

negative feedback loop suppress TNFα production and processing.95 Hence, TNFα serves as its own

regulator.

Interleukin-1

IL-1 posseses similar functions to TNFα in mediating a proinflammatory host response to insult; it is

frequently released concomitantly with TNFα (Table 7-6).110 The major source of IL-1 is the

mononuclear phagocyte. Synthesis and release are induced by LPS, cytokines such (TNFα, IL-2, TGF-β,

all the interferons), antigen–antibody complexes, C5, and hypoxia.95 IL-1 is also produced by

neutrophils, B cells, helper T cells, epithelial cells, fibroblast, renal mesangial cells, and endothelial

cells. There are two forms of IL-1; IL-1α and IL-1β. Both forms are active, bind to the same receptors

and mediate the same effects. Most IL-1 found in circulation is IL-1β.4

The two IL-1 receptors (IL-1R) are members of the Ig superfamily. IL-1RI is universally expressed and

transduces the majority of IL-1 responses.111,112 IL-1RII expression is restricted to B cells, but may be

induced on other cells. There is little evidence that this latter receptor serves any function, and in fact,

may serve as a decoy.113 The cytoplasmic portion of IL-1RI is homologous to a domain of TLR, which

mediate the cellular responses to endotoxin (Fig. 7-7). Engagement of IL-1 with IL-1RI induces the

activation of the IL-1 receptor-associated kinase (IRAK) and the subsequent induction of the

transcription factors NFκB and AP-1.4,112

Figure 7-7. Toll-like receptor (TLR) signaling pathway. (Redrawn from Abbas AK, Lichtman AH. Cellular and Molecular Immunology.

5th ed. Philadelphia, PA: Saunders; 2003.)

The functions of IL-1 mirror those of TNFα, and synergy between the two cytokines is evident.110 IL-1

activates endothelial cells to increase cell surface expression of adhesion molecules and the production

of prostaglandins, PAF, and a variety of CSFs. In doing so, it facilitates the recruitment and activation of

appropriate leukocyte populations for specific localized immune responses. IL-1 also induces a

procoagulant state by suppressing fibrinolysis through enhanced plasminogen activator inhibitor-1 and

decreased tissue-type plasminogen activator activity. It increases thrombosis by stimulating tissue

factor–like procoagulant and thromboplastin production and suppressing thrombomodulin release. It

induces the synthesis of PAF, a potent vasoconstrictor and stimulus for platelet and leukocyte activation.

However, similar to TNFα, it also stimulates the production of prostacyclin and urokinase-type

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plasminogen activator, which promotes an antithrombotic state.114 At larger concentrations, its effects

become systemic causing fever, the synthesis of acute-phase proteins, cachexia, myalgia, somnolence,

and hypotension. It stimulates arachidonic acid and prostaglandin metabolism, and the release of

pituitary stress hormones. It stimulates collagenase release and is a potent mitogen for neutrophils.

Though similar in effect to TNFα, probably by activating similar signaling cascades and transcription

factors, IL-1 does not induce apoptosis. Even at high concentrations IL-1 does not cause the physiologic

derangements of septic shock.39,110

Mononuclear cells produce the natural inhibitor of IL-1, IL-1ra. This IL-1 structural homologue is an

inactive competitive inhibitor and may function as an endogenous regulator of IL-1. As with TNFα,

attempts to inhibit IL-1 have not been of clinical benefit in human trials of sepsis.39

Chemokines

This is a large family of cytokines that primarily govern leukocyte chemotaxis, hence the name115–119

(Table 7-6). Those bound on the endothelial surface induce leukocyte integrins to express a high-affinity

state for their ligands, which is critical for tight leukocyte adherence and subsequent migration into the

extravascular space. However, they also assist in orchestrating the migration of immune cells into

lymphoid organs. Unlike other chemoattractants, members of this family possess a degree of specificity,

influencing the recruitment of discrete subsets of leukocytes. They mediate their effects both directly

and indirectly through the induction of other mediators such as histamine and ROS. Though some

chemokines, in particular those regulating cell traffic through tissues, are constitutively produced (MIP3β and RANTES), most necessitate cellular stimulation for synthesis and release, in particular, those

involved in inflammatory reactions. They are typically produced by macrophages, leukocytes,

endothelial cells, fibroblasts, and many other cell types stimulated by LPS, phagocytosis, and

inflammatory cytokines such as IL-1, TNFα, IL-6, and IFNγ.39

Chemokines can be classified into four families based on the number and location of N-terminal

cysteine residues. The two major families are the CC chemokines, in which the cysteine residues are

adjacent, and the CXC chemokines, in which one amino acid is interposed between these cysteine

residues. This amino acid sequence appears to account for the disparate influence, either promotion or

inhibition, on neutrophil chemotaxis. The three amino acids that immediately precede the first cysteine

are critical in defining receptor binding and neutrophil activation.120,121 This area has been designated

the ELR motif. The other two chemokine families are represented by lymphotactin (C chemokine) and

fractalkine (CX3C chemokine).39

Chemokine receptors are seven transmembrane receptors that signal by G proteins and the formation

of the second messengers, IP3 and DAG (Fig. 7-5). Currently 6 CXC chemokine receptors, 11 CC, and 1

receptor each for the last two subfamilies have been identified and defined. The pattern of cellular

expression of the receptors determines the specificity of the cellular response to binding.4,121

CXC chemokines primarily govern the chemoattraction and activation of neutrophils, and to a lesser

degree lymphocytes, in particular T cells. At least 12 different chemokines have been identified. They

are clustered on chromosome 4 and demonstrate 20% to 50% homology at the amino acid level. IL-8 is

the prototypical CXC chemokine.98 It is produced by an array of immune and nonimmune cells including

monocytes, alveolar macrophages, neutrophils, keratinocytes, mesangial cells, epithelial cells,

fibroblasts, and endothelial cells. TNFα and IL-1 are key molecules for inducing IL-8. It is chemotactic

for all granulocytes and influences nearly every aspect of neutrophil function. It stimulates neutrophil

degranulation, phagocytosis, transendothelial migration and shedding of L-selectin, upregulation of β2

integrins, and augments superoxide production. It is also a potent angiogenic factor. It binds to both the

CXCR1 and CXCR2, receptors that also engage the chemokines GCP-2, GRO-α, and ENA-78. ENA-78 is a

potent neutrophil chemotaxin produced by the endothelium in response to TNFα or IL-1, neutrophils, or

monocytes. Studies have demonstrated that ELR-containing CXC chemokines are angiogenic, whereas

those lacking this motif are angiostatic.39,95,120–122

The interferon-influenced chemokines, IP-10 and Mig do not target neutrophils, and the ELR motif is

absent. They induce IFNγ production and may play a more prominent role in mediating the

inflammatory response to viral infections and autoimmune disorders. Mig is chemotactic for tumor

infiltrating lymphocytes, activated T cells, and monocytes and promotes CTL activity. IP-10 is

chemotactic for monocytes, T cells, and NK cells and augments T-cell adhesion. Both chemokines bind

the CXCR3 receptor found on IL-2–activated T cells. IFNγ attenuates the expression of both IL-8 and

ENA-78, and hence may serve as an important mechanism to the control and regulate inflammation.39,95

Stromal cell–derived factor-1 (SDF-1) is the only known ligand for the CXCR4 receptor and in the

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