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Atypical chemokine receptors (ACKRs) are seven-transmembrane cell surface protein receptors expressed in immune cells, normal mesenchymal cells, and several tumor cells. As of this writing, six ACKRs have been characterized by diverse activities. They bind both cysteine-cysteine (CC) type and cysteine-X-cysteine (CXC)-type chemokines, either alone, or together with a ligand bound-functional G-protein coupled (typical) chemokine receptor. The major structural difference between ACKRs and typical chemokine receptors is the substituted DRYLAIV amino acid motif in the second intracellular loop of the ACKR. Due to this substitution, these receptors cannot bind Gαi-type G-proteins responsible for intracellular calcium mobilization and cellular chemotaxis. Although initially characterized as non-signaling transmembrane receptors (decoy receptors) that attenuate ligand-induced signaling by GPCRs, studies of all ACKRs have shown ligand-independent and ligand-dependent transmembrane signaling in both non-tumor and tumor cells. The precise function and mechanism of the differential expression of ACKRs in many tumors are not understood well. The use of antagonists of ACKRs ligands has shown limited antitumor potential; however, depleting ACKR expression resulted in a reduction in experimental tumor growth and metastasis. The ACKRs represent a unique class of transmembrane signaling proteins that regulate growth, survival, and metastatic processes in tumor cells, affecting multiple pathways of tumor growth. Therefore, closer investigations of ACKRs have a high potential for identifying therapeutics which affect the intracellular signaling, preferentially via the ligand-independent mechanism.

Viruses have evolved numerous mechanisms to evade the immune response, including proteins that target the function of cytokines. This article provides an overview of the different strategies used by viruses to block the induction of cytokines and immune signals triggered by cytokines. Examples of virus evasion proteins are presented, such as intracellular proteins that block signal transduction and immune activation mechanisms, secreted proteins that mimic cytokines, or viral decoy receptors that inhibit the binding of cytokines to their cognate receptors. Virus-encoded proteins that target cytokines play a major role in immune modulation, and their contributions to viral pathogenesis, promoting virus replication or preventing immunopathology, are discussed.

Interleukin-1 (IL-1) was the first interleukin to be identified and characterized as a major endogenous pyrogen and a potent proinflammatory and pleiotropic molecule involved in resistance to microbes and in injury. Since IL-1's discovery, the IL-1 system has impressively grown and now its ligands and receptors are recognized as large and complex families of molecules involved in host responses in infections and inflammation, as well as in the activation of innate and adaptive cells. Indeed, all cells of the innate immune system express and/or are affected by IL-1 family members, and IL-1 family members play a key role in the differentiation and function of polarized innate and adaptive cells. The IL-1 family includes ligands with agonist activity, receptor antagonists, and an anti-inflammatory cytokine. Members of the IL-1 receptor family include signaling receptor complexes, decoy receptors, and negative regulators. The IL-1 system is tightly controlled at different levels by antagonists, decoy receptors, scavengers, and dominant negative molecules. Indeed, the deregulated or excessive activation of the IL-1 system is the potential cause of dangerous and detrimental local or systemic inflammatory reactions, as well as autoimmune or allergic responses, and anti-IL-1 therapies have had a tremendous impact on inflammatory diseases.

Recombinant protein therapeutics cannot enter brain drug development because these large molecule drugs do not cross the blood-brain barrier (BBB). However, recombinant proteins can be reengineered as BBB-penetrating IgG fusion proteins, where the IgG part is a genetically engineered monoclonal antibody (MAb) against an endogenous BBB receptor, such as the human insulin receptor (HIR) or the transferrin receptor (TfR). The IgG binds the endogenous insulin receptor or TfR to trigger transport across the BBB and acts as a molecular Trojan horse (MTH) to ferry into brain the fused protein therapeutic. The most potent MTH to date is a MAb against the HIR, designated the HIRMAb, which is active in humans and Old World primates, such as the Rhesus monkey. There is no known MAb against the mouse insulin receptor. For drug delivery in the mouse, protein therapeutics are fused to a chimeric MAb against the mouse TfR, designated the cTfRMAb. The HIRMAb or cTfRMAb Trojan horses have been engineered and expressed as fusion proteins with multiple classes of protein therapeutics, including lysosomal enzymes, neurotrophins, decoy receptors, single chain Fv therapeutic antibodies, and avidin. The pharmacokinetic (PK) properties of the IgG fusion proteins differ from that of typical MAb drugs and resemble the PK profiles of small molecules due to rapid uptake by peripheral tissues, as well as brain. The brain uptake of the IgG fusion proteins, 2-3% of injected dose/brain, is comparable to the brain uptake of small molecules. The IgG fusion proteins have been administered chronically in mouse models, and the immune response is low titer and has no effect on the fusion protein clearance from blood or brain uptake in vivo. The BBB MTH technology enables the reengineering of a wide spectrum of recombinant protein therapeutics for targeted drug delivery to the brain.

Decoy receptors are "silent scavengers" of CC chemokines and cytokines, which play a key role in damping inflammation and tissue damage. In this review we discuss on recent findings demonstrating that these receptors set the balance between antimicrobial resistance, immune activation and inflammatory response in Mycobacterium tuberculosis infection.

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a clinically useful cytokine. TRAIL induces apoptosis in a wide variety of transformed cells, but does not cause toxicity to most normal cells. Recent studies show that death receptors (DR4 and DR5), decoy receptors (DcR1 and DcR2), and death inhibitors (FLIP, FAP-1, and IAP) are responsible for the differential sensitivity to TRAIL of normal and tumor cells. Several researchers have also shown that genotoxic agents, such as chemotherapeutic agents and ionizing radiation, enhance TRAIL-induced cytotoxicity by increasing DR5 gene expression or decreasing the intracellular level of FLIP, an antiapoptotic protein. Previous studies have shown that ceramide helps to regulate a cell's response to various forms of stress. Stress-induced alterations in the intracellular concentration of ceramide occur through the activation of a variety of enzymes that synthesize or catabolize ceramide. Increases in intracellular ceramide levels modulate apoptosis by acting through key proteases, phosphatases, and kinases. This review discusses the interaction between TRAIL and ceramide signaling pathways in regulating apoptotic death.

The discovery of an agent that selectively kills tumor cells and not normal cells is the dream of every cancer researcher. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), first discovered in 1995, was heralded as a selective killer of tumor cells, and its potential is still thought to be high. Almost immediately, broad efforts were made to understand its activity at the molecular level. TRAIL has been shown to interact with the cell surface through five distinct receptors, named death receptor (DR) 4, DR5, decoy receptor (Dc)R1, DcR2, and osteoprotegrin. It activates nuclear factor (NF)-kappaB, c-Jun N-terminal kinases, and apoptosis. The apoptotic signals are mediated through Fas-associated death domain protein (FADD)-mediated recruitment of caspase-8 and caspase-3. Additionally, caspase-8 can cleave Bcl-2 homology domain 3 (BH3)-interfering domain death agonist (Bid), and the cleaved Bid then causes the release of mitochondrial cytochrome c, leading to the activation of pro-caspase-9, which can then activate pro-caspase-3. TRAIL-induced apoptosis is negatively regulated by numerous cellular factors including decoy receptors, cellular FADD-like interleukin 1 beta-converting enzyme (FLICE) interacting protein (cFLIP), cellular inhibitor of apoptosis protein (cIAP), X-linked IAP (XIAP), survivin, and NF-kappaB. Second mitochondria-derived activator of caspases (Smac)?direct IAP binding protein with low pI (DIABLO) mediates proapoptotic signals through inaction of IAP. How the TRAIL-induced apoptosis is downregulated by these factors is discussed in detail in this review. Whether TRAIL selectively kills tumor cells without harming normal cells is also discussed.

TRAIL-R3 is a decoy receptor for TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), a member of the tumor necrosis factor (TNF) ligand family. TRAIL induces apoptosis in a broad range of cancer cell lines, but not in many normal cells-a finding that generated extraordinary excitement about its potential as a specific antitumor agent. In several cell types, decoy receptors inhibit TRAIL-induced apoptosis by binding to it and preventing its binding to TRAIL proapoptotic or death receptors. However, recently published data regarding the role of these receptors in TRAIL-induced cellular death are contradictory. The key to resolving this controversy may lie in the regulation and cellular localization of TRAIL receptors. In this regard, cloning and analysis of the TRAIL-R3 promoter will help to identify the cellular factors that regulate its transcriptional expression. This chapter summarizes current knowledge in this field and outlines directions for future research.

Publisher Summary TRAIL is a recently identified member of the tumor necrosis factor (TNF) family, which consists of 281 (human TRAIL) or 291 (murine TRAIL) amino acids. The human TRAIL gene is located on chromosome 3 at position 3q26 and the human TRAIL protein has a calculated molecular mass of 32.5 kDa and isoelectric point of 7.63. TRAIL is primarily expressed as a type II membrane protein with a very short intracellular amino-terminal tail of 17 amino acids and an extracellular carboxy-terminal domain. TRAIL interacts with five distinct receptors: two death receptors (DR), and two decoy receptors (DcR) and osteoprotegerin (OPG), all belonging to the TNF receptor superfamily. TRAIL interacts via two cysteine-rich domains with DR4 or DR5 to form homotrimers. TRAIL also interacts with two decoy receptors (DcR). DcR1 (TRAIL-R3, LIT, TRID) is a glycosyl phosphatidylinositol (GPI)-anchored membrane protein. DcR2 (TRAIL-R4, TRUNDD) is a type I transmembrane protein of 386 amino acids with an extracellular domain similar to DR4 and DR5. DcR1 and DcR2 bind to TRAIL with high affinity, but they are unable to transduce an apoptotic signal. Overexpression of DcR2 results in cell resistance to TRAIL-induced apoptosis and deletion of the DcR2 cytoplasmic region does not abrogate the inhibitory activity of DcR2.

Publisher Summary The chapter provides an overview of chemokine receptor classication, genomic location, structure, expression, binding, function, viral mimics, therapeutic implications, and potential decoy receptors. It discusses a hypothesis that the chemokine system, like the IL-1 pathway, has endogenous decoy receptors in addition to the Duffy antigen. Understanding the multifaceted roles of chemokines and their receptors in vivo has been facilitated by the development of transgenic mice and targeted deletion/mutagenesis of chemokines and their receptors. Chemokines are subdivided into classes based on the relative positions of their N-terminal cysteine residues. Chemokine receptors have a structure similar to that of other G protein-coupled receptors. The structure of chemokine receptors is characteristic of receptors, such as rhodopsin and the muscarinic acetylcholine receptor, which are coupled with guanine nucleotide binding proteins (G proteins). Chemokine receptor expression varies with cell type and receptor. Some receptors are restricted to certain cell types while others are expressed on many cell types. Chemokine receptors play a major role in two infectious diseases that cause significant morbidity and mortality worldwide: human immunodeciency virus (HIV) and malaria. One of the accepted models for chemokine/chemokine receptor interaction is the two-step binding and signaling model. In this model, the chemokine binds to the initial binding site, and the ensuing conformational change allows the pharmacophore to interact with the transmembrane helices to trigger signal transduction.