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presence of IL-7 stimulates proliferation of pre–B-cell clones and growth of bone marrow B progenitor

cells. The receptor has gained much interest since it was identified as a coreceptor for HIV-1. PF4 and

neutrophil-activating protein-2 are CXC chemokines of platelet origin. PL-4 has angiostatic properties

and inhibits the growth of various cancer cell lines in a manner that appears to be related to its

angiostatic properties. It binds heparin with high affinity to stimulate coagulation.39

The CC chemokines recruit monocytes, granulocytes, T cells, NK cells and DCs. RANTES is produced

by stimulated T cells, platelets, and endothelial cells and is constitutively produced in resting T cells,

which implies a homeostatic function. MIP-1α and β are produced by activated T cells and are

chemotactic for neutrophils, monocytes, eosinophils, basophils, and T lymphocytes. They are also

mitogenic for hematopoietic progenitor cells and upregulate TNFα, IL-1, and IL-6. The MCP family of

chemokines influences the recruitment of monocytes and T cells. Their influence upon the function of

these target cells is dictated by the cell’s specific profile of receptor expression. MCP-1 is produced by

nonlymphocytic cells (endothelial cells, epithelial cells, fibroblasts, smooth muscle cells, macrophages

and mast cells). Binding to CCR1 enhances chemotaxis, whereas activation of CCR2 increases the release

of intracellular substances such as histamine and LTs from basophils.39

Lymphotactin is the only member of the C chemokine family and is produced by CD8+ lymphocytes,

thymocytes, and NK cells, and, to a lesser degree, by DC and activated mast cells. It selectively recruits

lymphoid cells.39

Fractalkine is the sole CX3C chemokine and is produced by the endothelium. In its membrane-bound

form it may act as a solid-phase adhesion molecule, but upon cleavage serves as a soluble

chemoattractant for lymphoid cells and monocytes.39

Interleukin-12 (NK Cell Stimulatory Factor, Cytotoxic Lymphocyte Maturation Factor)

IL-12 is integral in the innate immune response (Table 7-6). It is produced early during innate immune

reactions and is critical for initiating a sequence of responses involving macrophages, NK cells, and T

lymphocytes that results in the eradication of intracellular microbes. It stimulates subsequent adaptive

responses that confer further host protection against these pathogens. Hence, it is an important link

between innate and adaptive immune responses. IL-12 is primarily derived from activated mononuclear

phagocytes and DCs, and most importantly stimulates IFNγ from T cells and NK cells. There are two

pathways leading to IL-12 production: a T-cell dependent and an independent pathway. During innate

immunity, LPS, infection by intracellular bacteria, and viral infections may induce IL-12 production. In

addition, interactions between CD40 ligand and CD40 on activated lymphocytes and APC, respectively,

induce the release of APC IL-12.123,124 Thus, IL-12 is produced during the induction of and the effector

phases of cell-mediated immune response when APCs present antigens to T cells.4,39

The IL-12 receptor is a heterodimer composed of β1 and β2 subunits, the latter of which is involved

in signaling, although both are required for engaging ligand. The receptor signals through the

JAK/STAT pathway (Fig. 7-8).4 This signal transduction pathway is employed by numerous cytokines

including interferons, IL-6, IL-12, IL-2, IL-7, IL-9, IL-4, and IL-10. A characteristic of this cytokine is the

generation of a positive amplification loop, which heightens the inflammatory response. Expression of

the IL-12 receptor is induced by IFNγ. Activated NK cells and TH1 cells produce IFNγ that potentiates

macrophage IL-12 production. IL-12 stimulates further production of IFNγ by NK cells and T

lymphocytes, which continues to fuel the reaction in a positive feedback mechanism. Ultimately, IFNγ

activates macrophages to kill and degrade phagocytosed microbes. IL-12 potentiates bacterial LPSinduced macrophage TNFα production. IL-12 antagonists reduce mortality in experimental models of

LPS-induced septic shock; however, there is no evidence of their efficacy in human clinical trials.4

4 5 CD4+ helper T lymphocytes, under the influence of IL-12, differentiate into TH1 cells, which

subsequently activate phagocytes in cell-mediated immunity. It enhances the cytolytic functions of

activated NK cells and CD8+ CTLs, and suppresses TH2 cell differentiation and effector activity. The

inhibition of TH2 and IL-4 activity confers antiallergic properties to IL-12. IL-12 knockout mice

demonstrate diminished IFNγ production and defective TH1 cell development and cell-mediated

immunity against intracellular organisms.4,39

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Figure 7-8. JAK/STAT signaling pathway. JAK (Janus Kinase) components are associated in an inactive form with the cytoplasmic

portion of cytokine receptors. Cytokine binding leads to receptor aggregation. Adjacent JAK proteins become activated and

phosphorylate each other and tyrosine residues. Through the Src homology domain, STAT proteins bind phosphotyrosine residues

on the cytoplasmic portion of cytokine receptors. Bound STAT proteins are phosphorylated by bound JAK proteins and

subsequently dissociate. Phosphorylated STAT proteins dimerize and then move to the nucleus where they induce transcription by

binding to STAT binding regions within the promoter. (Redrawn from Abbas AK, Lichtman AH. Cellular and Molecular Immunology.

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

Interleukin-6

IL-6 regulates the acute-phase response to inflammation, characterized by altered thermoregulation

(i.e., fever), perturbation in nitrogen balance (i.e., cachexia and catabolism), and the generation of the

acute-phase reactants of innate immunity by the liver (Tables 7-6 and 7-7).95,125 It functions in both

innate and adaptive immunity to enable the host to recover. Despite in vitro data demonstrating that a

variety of cells can produce IL-6, the most prominent in vivo sources of IL-6 are monocytes and

macrophages stimulated with LPS or IL-1 or fibroblasts and endothelial cells stimulated with TNFα.126

Steroids inhibit the induction of IL-6. The receptor for IL-6 consists of cytokine-binding protein and a

signal-transducing subunit, which belong to the type I cytokine receptor family. It signals through the

JAK-STAT pathway (Fig. 7-8).4

In conjunction with IL-1 and TNFα, IL-6 regulates the systemic manifestations of the acute-phase

response.125 It potentiates the immune response by inducing B-cell differentiation and activating T cells.

It interacts with TNFα to enhance T-cell proliferation and promotes neutrophil activation and

accumulation. In adaptive immunity, IL-6 stimulates the growth of B lymphocytes that have

differentiated into antibody-producing plasma cells. IL-6 antagonizes LPS-induced TNFα production and

TNFα-induced IL-1 production.127,128

Table 7-7 Acute-Phase Proteins

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High Mobility Group Box 1 Protein

HMGB1 was initially identified as an architectural chromatin-binding factor that bends DNA and directs

protein assembly on specific DNA targets. It is abundant, ubiquitous, and evolutionarily conserved, as

evident by the 99% amino acid homology between rat and human proteins.56 Thirty years after its

original discovery, Tracey at al. demonstrated that HMGB1 acts as a late mediator of mortality in

murine endotoxemia and sepsis. HMGB1 appeared 8 hours poststimulation and plateaued at 16 to 32

hours, very distinct from the acute rise and fall of early mediators (TNFα, IL-1β) of severe sepsis and

septic shock.56 Recent studies show that systemic concentrations are elevated in those patients who die

of sepsis.129

HMGB1 is the prototypical DAMP. When cells die by necrosis (i.e., nonprogrammed cell death),

HMGB1 is released into the extracellular medium. In contrast, apoptotic cells modify their chromatin so

that HMGB1 irreversibly binds, and thus is not released.130,131 However, HMGB1 may also be released

by activated macrophages and NK cells, via an active process that necessitates shuttling the protein from

nucleus to cytoplasm; this event does not require further synthesis.130–132 Acetylation of HMGB1

appears essential for release, however acetylation of histones as occurs during apoptosis, strengthens its

interaction with chromatin and inhibits release.130,131 Interestingly, though apoptotic cells do not

release HMGB1, macrophages engulfing apoptotic cells do. Recent studies have shown that

nucleocytoplasmic shuttling of HMGB1 involves serine phosphorylation by CaMKIV that enables it to be

translocated to the cytoplasm by 14-3-3 and CRM1 chaperones.133,134 Subsequent release of cytoplasmic

HMGB1 appears to involve active secretion through a secretory lysosomal pathway.130,132

HMGB1 has many of the intercellular signaling activities characteristic of cytokines and therefore is

often classified as a proinflammatory cytokine and potent regulator of the inflammatory response. In

light of the fact that it is released by macrophages responding to bacterial challenge or by injured cells,

it may mediate inflammation consequent to sepsis or trauma. After release, signaling is thought to occur

by binding to RAGE with subsequent activation of p21ras, MEK, the MAPK kinases, and NFκB.106,135

This receptor is expressed on mononuclear phagocytes, vascular smooth muscle cells, and neurons.

Blocking antibodies to RAGE fails to completely prevent cellular activation suggesting the presence of

an alternate receptor. Recent studies suggest that both TLR2 and TLR4 may mediate HMGB1-induced

activation of NFκB in macrophages and neutrophils. This observation is very important as it

demonstrates that a receptor classically considered specific for microbial danger signals, may interact

with an endogenous molecule.56,106,135

HMGB1-RAGE interactions induce numerous proinflammatory events. Endothelial cells increase the

expression of adhesion molecules and secrete TNFα and IL-8.136 In neutrophils, HMGB1 activates

MAPKs and enhances the expression of proinflammatory cytokines in a NFκB-dependent manner. In

addition, it is chemotactic for neutrophils, monocytes, macrophages, and DCs.106 Intratracheal

administration of HMGB1 to LPS-resistant mice stimulated lung neutrophil accumulation and the local

production of proinflammatory cytokines.106 HMGB1 has potent immunostimulatory actions and

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