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promotes the maturation of both myeloid and plasmacytoid DCs. Systemic levels are markedly elevated

in patients who die of sepsis, and animal studies suggest that this association is causal.129 Recombinant

HMGB1 mimics the lethality of high-dose LPS and induces the release of TNFα by macrophages.

However, intravenous administration of HMGB1 does not cause shock like TNFα. More recent data call

into question whether HMGB1 itself can directly promote the secretion of proinflammatory cytokines

(TNFα, IL-1α/β, IL-6, IL-8) and chemokines (MIP1α/β) as initially reported. A direct proinflammatory

activity of HMGB1 has not been reproduced consistently, raising some concern that this might be based

on the formation of specific complexes with other molecules such as LPS. Recent studies show that

highly purified recombinant HMGB1 has very weak direct proinflammatory activity.137

In a series of elegant studies, anti-HMGB1 antibodies conferred a dose-dependent protection in animal

models of endotoxemia, even when the first dose of anti-HMGB1 antibodies was delayed for 2 hours.57

This occurred without changes in TNFα, IL-1β, or MIP-2 concentrations. Even more striking are the in

vivo CLP models, in which anti-HMGB1 administration up to 24 hours after CLP significantly increased

survival, 72% versus 28%.57 This wider therapeutic window may enable the development of inhibitors

of HMGB1 for treat of sepsis.106,138–140 These observations have stimulated the search for other

inhibitors of HMGB1. Ethyl pyruvate a nontoxic food additive, dose dependently inhibits HMGB1

release, and confers significant protection against the lethality of sepsis, even when the first dose is

administered 24 hours after the onset of sepsis. In addition, it inhibits the translocation of NFκB and p38

MAPK signaling.106,138,141,142

HMGB1 may also serve as a danger signal for other perturbations in homeostasis, as it can also be

released passively by necrotic or injured cells but not apoptotic cells.131,140,143,144 Hypoacetylation of

chromatin on the induction of apoptosis enhances HMGB1 binding, thereby preventing release during

apoptotic processes. Thus, HMGB1 binding to chromatic depends on the viability of the cell and clearly

distinguishes necrotic from apoptotic cells. This enables the innate immune response to respond to

injury and further induce inflammation.131,140,143,144

HMGB1 is also elevated during hemorrhage shock.145 In a clinical case, serum HMGB1 levels

increased significantly within 24 hours of hemorrhagic shock and returned toward basal levels as the

clinical condition improved.146 HMGB1 also appears to mediate cell damage and death in other

noninfectious insults. In a model of warm liver ischemia reperfusion, HMGB1 inhibition attenuates

hepatocellular injury.32 Interestingly, this protection, as well as reduced systemic concentrations of

HMGB1, was also afforded by inhibiting CaMK.32

High levels of HMGB1 have also been found in other conditions of sterile inflammation such as

rheumatoid arthritis.147–149 In human arthritis, overexpression of HMGB1 at the site of joint

inflammation may be detected in the synovial fluid of rheumatoid arthritis patients.148,149 HMGB1 may

in fact amplify the effect of local cytokines as suggested by its ability to stimulate macrophages derived

from synovial fluid of rheumatoid arthritis patients to release TNFα, IL-1β, and IL-6.147,150 Hence,

HMGB1 may serve as a signal of danger from endogenous threats or perturbations.

Interleukin-15

IL-15 is produced by various cells in response to LPS and other stimuli, though the principal cellular

source is mononuclear phagocytes. (Table 7-6). It is structurally homologous to IL-2, as is its receptor

and the IL-2R. IL-15 stimulates the proliferation of NK cells similar to the manner by which IL-2

functions later in the adaptive immune response. It also acts as a T-cell growth and survival factor

especially for long-lived memory CD8+ T cells.4

Interleukin-18

IL-18 is structurally homologous to IL-1 and utilizes a similar IRAK signaling pathway (Table 7-6).

Macrophages responding to microbial challenge or exposure to LPS are the principal source. Its primary

function is to stimulate the production of IFNγ by NK cells and T cells, and in synergizing with IL-12,

augments cell-mediated immunity. Knockout mice lacking IL-18 are deficient in IFNγ production, and

concomitant IL-12 deficiency eliminates all IFNγ production and any TH1 response.4

Interferons (Type I)

Type I interferons possess potent antiviral and antitumor properties (Table 7-6). It is from this ability to

“interfere” with viral infection that the name is derived. They are subcategorized into α and β

interferons. Mononuclear phagocytes are the major source of interferon α, whereas many cell types

produce interferon β. The most potent stimulus inducing the synthesis and release of either is viral

infection, particularly double-stranded RNA produced during viral replication. Other inducers include IL197

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1, TNFα, LPS, and antigen-activated T cells. Both groups bind to the same cell surface receptor and

induce similar responses by signaling through the JAK/STAT pathway (Fig. 7-8).

These cytokines provide the first line of defense against viral infection and promote cell-mediated

immunity against intracellular pathogen. They are secreted from virally infected cells to protect

neighboring uninfected ones by inducing the synthesis of a number of enzymes that interfere with viral

RNA or DNA transcription and viral replication. Through enhanced expression of class I MHC molecules,

the type 1 interferons facilitate recognition of class I–associated viral antigens on infected cells by CTLs

and increase the efficiency of CTL-mediated killing. Type I interferon stimulates the development of TH1

cells by promoting these cells to express IL-12 receptor. They can also stimulate B-cell development,

proliferation, and immunoglobulin heavy chain switching from IgM to IgG.151–153 Knockout mice

lacking the receptor for these cytokines are susceptible to viral infections. Interferons are currently in

clinical use for hepatitis B and C infection, multiple sclerosis, CML, and Kaposi’s sarcoma.151–153

Interleukin-10 (Cytokine Synthesis Inhibiting Factor)

IL-10 inhibits activated macrophages and APC and functions in a counterregulatory mechanism to

suppress innate immune reactions (Table 7-6). It is produced mainly by macrophages, and hence

functions by negative feedback. T lymphocytes, particularly the TH2 subset, B cells, and some other

nonlymphoid cells produce IL-10, in response to a variety of stimuli including LPS, TNFα, IL-2, IL-4, and

IL-13.

IL-10 binds to a type II (interferon) receptor. Though the manner by which it effects curtailment of

the inflammatory response is unknown, its presence inhibits NKκB activation and the generation of

inflammatory mediators. Thus, it may inhibit, in some manner, the activation of signal transduction

cascades and gene activation in proinflammatory pathways.4,154

IL-10 terminates many of the functions of activated macrophages and participates in reestablishing

homeostasis as the infection resolves. It downregulates proinflammatory cytokine (TNFα, IL-1, IL-6, and

IL-8) production, suppresses the production of IL-12, and inhibits IFNγ production and the innate and

cell-mediated immune responses.4,59,95 It represses the expression of costimulators and class II MHC

molecules on APC, thereby terminating T-cell activation and inhibiting cell-mediated immunity.4 In

neutrophils it inhibits cytokine release, superoxide generation, migration, and even survival.155 In

combination with IL-4 it inhibits IFNγ release and IL-12 production to limit differentiation and function

of TH1 cells, favoring a TH2 profile.59

IL-10 knockout mice develop inflammatory bowel disease, which is hypothesized to result from

unregulated macrophage reaction to enteric microbes.156 In observational studies of ARDS or MODS,

serum IL-10 levels were often elevated, and those patients with the highest systemic concentrations

died.154 It is unclear whether this is actually a pathologic response, or merely a marker of disease

severity. Contemporary belief is that IL-10 is not a mediator of immunosuppression, but rather,

important for immunoregulation.

Late Cytokines/Adaptive Immunity

Interleukin-2 (T-Cell Growth Factor)

IL-2 stimulates the growth and proliferation of T lymphocytes and is responsible for T-cell clonal

expansion after antigen recognition (Table 7-6).157 IL-2 is produced by CD4+, and to a lesser extent

CD8+ T cells. The receptor is heterotrimeric, consisting of three noncovalently associated proteins α, β,

and γ. The α and β chains are involved in cytokine binding, and the β and γ chains mediate signal

transduction.4 Antigen recognition enhances the expression of functional IL-2 receptors, which confers a

degree of specificity, as those T cells recognizing antigen are preferentially induced to proliferate in

response to IL-2. Though, the α chain appears on T cell activation and binds IL-2, signal generation

necessitates the β and γ chains. Cells expressing the complete α, β, and γ complex bind IL-2 with higher

affinity (kD of 10−11 M), and growth stimulation of such cells occurs at a low IL-2 concentration.4 Upon

antigen receptor–mediated T-cell activation, IL-2R α is rapidly upregulated, which reduces the

concentration of IL-2 needed to stimulate growth. Therefore, antigen-stimulated T cells are more

responsive to IL-2 than naïve T cells. This receptor signals through numerous signal transduction

pathways including the JAK/STAT and MAP kinase pathways (Figs. 7-5 and 7-8).

IL-2 functions in an autocrine and paracrine fashion to induce the proliferation of the antigen-specific

cells. After exposure to IL-1, there is a rise in cyclins and activation of cyclin-dependent kinases that

stimulates the progression of the cell cycle from the G1 to the S phase. A reduction in p27, an inhibitor

of cyclin–kinase complexes, facilitates this progression, and the induction of Bcl-2, an antiapoptotic

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