Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Inflammatory pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,171 records · Page 65Linked to original sources
PubMed2003

Radical causes of cancer.

Free radicals are ubiquitous in our body and are generated by normal physiological processes, including aerobic metabolism and inflammatory responses, to eliminate invading pathogenic microorganisms. Because free radicals can also inflict cellular damage, several defences have evolved both to protect our cells from radicals--such as antioxidant scavengers and enzymes--and to repair DNA damage. Understanding the association between chronic inflammation and cancer provides insights into the molecular mechanisms involved. In particular, we highlight the interaction between nitric oxide and p53 as a crucial pathway in inflammatory-mediated carcinogenesis.

Animals↗
PubMed2001

Tissue factor pathway inhibitor: an update of potential implications in the treatment of cardiovascular disorders.

Tissue factor (TF) plays a crucial role in the pathogenesis of thrombotic, vascular and inflammatory disorders. Thus, the inhibition of this membrane protein provides a unique therapeutic approach for prophylaxis and/or treatment of various diseases. Tissue factor pathway inhibitor (TFPI), the only endogenous inhibitor of the TF/Factor VIIa (FVIIa) complex, has recently been characterised biochemically and pharmacologically. Studies in patients demonstrated that both TF and TFPI may be indicators for the course and the outcome of cardiovascular and other diseases. Based on experimental and clinical data, TFPI might become an important drug for several clinical indications. TFPI is expected to inhibit the development of post-injury intimal hyperplasia and thrombotic occlusion in atherosclerotic vessels as well as to be effective in acute coronary syndromes, such as unstable angina and myocardial infarction. Of special interest is the inhibition of TF-mediated processes in sepsis and disseminated intravascular coagulation (DIC), which are associated with the activation of various inflammatory pathways as well as of the coagulation system. A Phase II trial of the efficacy of TFPI in patients with severe sepsis showed a mortality reduction in TFPI- compared to placebo-treated patients and an improvement of organ dysfunctions. TFPI can be administered exogenously in high doses to suppress TF-mediated effects, alternatively high amounts of TFPI can be released from intravascular stores by other drugs, such as heparin and low molecular weight heparins (LMWH). Using this method high concentrations of the inhibitor are provided at sites of tissue damage and ongoing thrombosis. At present, clinical studies with TFPI are rather limited so that the clinical potential of the drug cannot be assessed properly. However, TFPI and its variants are expected to undergo further development and to find indications in various clinical states.

Animals↗
PubMed2001

Green tea polyphenolic antioxidants and skin photoprotection (Review).

Green tea is consumed as a popular beverage worldwide particularly in Asian countries like China, Korea, Japan and India. It contains polyphenolic compounds also known as epicatechins, which are antioxidant in nature. Many laboratories have shown that topical treatment or oral consumption of green tea polyphenols inhibits chemical carcinogen- or ultraviolet radiation-induced skin tumorigenesis in different animal models. Studies have shown that green tea extract also possesses anti-inflammatory activity. These anti-inflammatory and anti-carcinogenic properties of green tea are due to their polyphenolic constituents present therein. The major and most chemopreventive constituent in green tea responsible for these biochemical or pharmacological effects is (-)-epigallocatechin-3-gallate (EGCG). Understanding the molecular mechanisms of these effects of green tea is a subject of investigation in many laboratories. Treatment of green tea polyphenols to skin has been shown to modulate the biochemical pathways involved in inflammatory responses, cell proliferation and responses of chemical tumor promoters as well as ultraviolet (UV) light-induced inflammatory markers of skin inflammation. Topical treatment with EGCG on mouse skin also results in prevention of UVB-induced immunosuppression, and oxidative stress. The protective effects of green tea treatment on human skin either topically or consumed orally against UV light-induced inflammatory or carcinogenic responses are not well understood. Based on documented extensive beneficial effects of green tea on mouse skin models and very little in human skin, many pharmaceutical and cosmetic companies are supplementing their skin care products with green tea extracts. Therefore, the focus of this communication is to review and analyze the photoprotective effects of green tea polyphenols to skin.

Anti-Inflammatory Agents↗
PubMed2006

Unloading kinesin transported cargoes from the tubulin track via the inflammatory c-Jun N-terminal kinase pathway.

Axonal transport of mitochondria and synaptic vesicle precursors via kinesin motor proteins is essential to keep integrity of axons and synapses. Disturbance of axonal transport is an early sign of neuroinflammatory and neurodegenerative diseases. Treatment of cultured neurons by the inflammatory cytokine tumor necrosis factor-alpha (TNF) stimulated phosphorylation of c-Jun N-terminal kinase (JNK) in neurites. TNF treatment induced dissociation of the heavy chain kinesin family-5B (KIF5B) protein from tubulin in axons but not cell bodies as determined by lifetime-based Förster resonance energy transfer (FRET) analysis. Dissociation of KIF5B from tubulin after TNF treatment was dependent on JNK activity. Furthermore, TNF inhibited axonal transport of mitochondria and synaptophysin by reducing the mobile fraction via JNK. Thus, TNF produced by activated glial cells in inflammatory or degenerative neurological diseases acts on neurites by acting on the kinesin-tubulin complex and inhibits axonal mitochondria and synaptophysin transport via JNK.

Animals↗
PubMed2007

MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists.

TLRs sense components of microorganisms and are critical host mediators of inflammation during infection. Different TLR agonists can profoundly alter inflammatory effects of one another, and studies suggest that the sequence of exposure to TLR agonists may importantly impact on responses during infection. We tested the hypothesis that synergy, priming, and tolerance between TLR agonists follow a pattern that can be predicted based on differential engagement of the MyD88-dependent (D) and the MyD88-independent (I) intracellular signaling pathways. Inflammatory effects of combinations of D and I pathway agonists were quantified in vivo and in vitro. Experiments used several D-specific agonists, an I-specific agonist (poly(I:C)), and LPS, which acts through both the D and I pathways. D-specific agonists included: peptidoglycan-associated lipoprotein, Pam3Cys, flagellin, and CpG DNA, which act through TLR2 (peptidoglycan-associated lipoprotein and Pam3Cys), TLR5, and TLR9, respectively. D and I agonists were markedly synergistic in inducing cytokine production in vivo in mice. All of the D-specific agonists were synergistic with poly(I:C) in vitro in inducing TNF and IL-6 production by mouse bone marrow-derived macrophages. Pretreatment of bone marrow-derived macrophages with poly(I:C) led to a primed response to subsequent D-specific agonists and vice versa, as indicated by increased cytokine production, and increased NF-kappaB translocation. Pretreatment with a D-specific agonist augmented LPS-induced IFN-beta production. All D-specific agonists induced tolerance to one another. Thus, under the conditions studied here, simultaneous and sequential activation of both the D and I pathways causes synergy and priming, respectively, and tolerance is induced by agonists that act through the same pathway.

Animals↗
PubMed2002

Autocrine production of IFN-gamma by macrophages controls their recruitment to kidney and the development of glomerulonephritis in MRL/lpr mice.

Anti-DNA autoantibody production is a key factor in lupus erythematosus development; nonetheless, the link between glomerular anti-DNA autoantibody deposition and glomerulonephritis development is not understood. To study the inflammatory and destructive processes in kidney, we used IFN-gamma(+/-) MRL/lpr mice which produce high anti-DNA Ab levels but are protected from kidney disease. The results showed that defective macrophage recruitment to IFN-gamma(+/-) mouse kidney was not caused by decreased levels of monocyte chemoattractant protein-1, a chemokine that controls macrophage migration to MRL/lpr mouse kidney. To determine which IFN-gamma-producing cell type orchestrates the inflammation pathway in kidney, we transferred IFN-gamma(+/+) monocyte/macrophages or T cells to IFN-gamma(-/-) mice, which do not develop anti-DNA autoantibodies. The data demonstrate that IFN-gamma production by infiltrating macrophages, and not by T cells, is responsible for adhesion molecule up-regulation, macrophage accumulation, and inflammation in kidney, even in the absence of autoantibody deposits. Therefore, in addition to monocyte chemoattractant protein-1, macrophage-produced IFN-gamma controls macrophage migration to kidney; the degree of IFN-gamma production by macrophages also regulates glomerulonephritis development. Our findings establish the level of IFN-gamma secretion by macrophages as a link between anti-DNA autoantibody deposition and glomerulonephritis development, outline the pathway of the inflammatory process, and suggest potential treatment for disease even after autoantibody development.

Animals↗
PubMed2003

Complement factor C5a mediates renal ischemia-reperfusion injury independent from neutrophils.

The complement system has been shown to mediate renal ischemia-reperfusion (I/R) injury. However, the contribution of complement factor C5a to I/R injury, in particular in the kidney, remains to be established. In this study, we investigated the impact of blocking the C5aR pathway on the inflammatory response and on the renal function in a murine model of I/R injury. First, we analyzed C5aR expression in kidneys of healthy mice. Intriguingly, we found expression on mesangial, as well as on tubular epithelial, cells. After I/R injury, C5aR expression was up-regulated in tubular epithelial cells. In addition, mRNA levels of CXC chemokines and TNF-alpha increased significantly and kidneys were heavily infiltrated by neutrophils. Blocking the C5aR pathway by a specific C5a receptor antagonist (C5aRA) abrogated up-regulation of CXC chemokines but not of TNF-alpha and reduced neutrophil infiltration by >50%. Moreover, application of the C5aRA significantly reduced loss of renal function. This improvement of function was independent of the presence of neutrophils because neutrophil depletion by mAb NIMP-R14 did not affect the protective effect of C5aRA treatment. Furthermore, blocking of the C5aR pathway had no influence on renal apoptosis. These data provide evidence that C5a is crucially involved in the pathogenesis of renal I/R injury by modulation of neutrophil-dependent as well as neutrophil-independent pathways, which include the regulation of CXC chemokines but not TNF-alpha or apoptotic pathways.

Animals↗
PubMed2025

Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms.

"Trained immunity" of innate immune cells occurs through a sequential two-step process where an initial pathogenic or sterile inflammatory trigger is followed by an amplified response to a later un-related secondary pathogen challenge. The memory effect is mediated at least in part through epigenetic modifications of the chromatin landscape. Here, we investigated the role of the epigenetic modifier Setdb2 in microbial (β-glucan) or sterile trigger (Western-diet-WD/oxidized-LDL-oxLDL)-induced trained immunity of macrophages. Using genetic mouse models and genomic analysis, we uncovered a critical role of Setdb2 in regulating proinflammatory and metabolic pathway reprogramming. We further show that Setdb2 regulates trained immunity through two different complementary mechanisms: one where it positively regulates glycolytic and inflammatory pathway genes via enhancer-promoter looping, and is independent of its enzymatic activity; while the second mechanism is associated with both increased promoter associated H3K9 methylation and repression of interferon response pathway genes. Interestingly, while both mechanisms occur in response to pathogenic training, only the chromatin-looping mechanism operates in response to the sterile inflammatory stimulus. These results reveal a previously unknown bifurcation in the downstream pathways that distinguishes between pathogenic and sterile inflammatory signaling responses associated with the innate immune memory response and may provide potential therapeutic opportunities to target cytokine vs. interferon pathways to limit complications of chronic inflammation.

Setdb2↗
PubMed1995

Role of allergy in nasal polyposis: a review.

We propose a multivariate theory for the pathogenesis of nasal polyps. Turbulent flow of air in the lateral wall of the nose or viral-bacterial-host interactions produce an inflammatory change in the mucosa of the lateral wall of the nose. Ulceration and prolapse of the submucosa with reepithelialization and new gland formation may then follow. The structural cells of the nasal polyp, including epithelial cells and fibroblasts, have the ability to produce messenger RNA for granulocyte-monocyte colony-stimulating factor and other cytokines. Stimulation of such an effector capability by structural cell-derived cytokines would undoubtedly represent a major amplification pathway of the inflammatory response in nasal polyps. Allergy may be one mechanism for the development of this cascade of events. This microenvironmental structural inflammatory response in the nasal polyp, in turn, can affect the bioelectric integrity of the Na+ and Cl- channels at the luminal surface of the respiratory epithelial cell. The change in the Na+ absorption, which has been demonstrated in our studies, may result in an increased movement of water into the cell and into the interstitial fluid. The resultant edema can lead to growth and enlargement of the nasal polyp. Finally, the rapid recurrence of nasal polyps despite adequate surgery may reflect some intrinsic phenotypic characteristic of nasal epithelial cells in the lateral wall of the nose, which is likely to be under genetic control.

Epithelium↗
PubMed2006

Clinical review: molecular mechanisms underlying the role of antithrombin in sepsis.

In disseminated intravascular coagulation (DIC) there is extensive crosstalk between activation of inflammation and coagulation. Endogenous anticoagulatory pathways are downregulated by inflammation, thus decreasing the natural anti-inflammatory mechanisms that these pathways possess. Supportive strategies aimed at inhibiting activation of coagulation and inflammation may theoretically be justified and have been found to be beneficial in experimental and initial clinical studies. This review assembles the available experimental and clinical data on biological mechanisms of antithrombin in inflammatory coagulation activation. Preclinical research has demonstrated partial interference of heparin--administered even at low doses--with the therapeutic effects of antithrombin, and has confirmed--at the level of cellular mechanisms--a regulatory role for antithrombin in DIC. Against this biological background, re-analyses of data from randomized controlled trials of antithrombin in sepsis suggest that antithrombin has the potential to be developed further as a therapeutic agent in the treatment of DIC. Even though there is a lack of studies employing satisfactory methodology, the results of investigations conducted thus far into the mechanisms of action of antithrombin allow one to infer that there is biological plausibility in the value of this agent. Final assessment of the drug's effectiveness, however, must await the availability of positive, prospective, randomized and placebo-controlled studies.

Animals↗
PubMed2006

The universal NF-kappaB inhibitor a20 protects from transplant vasculopathy by differentially affecting apoptosis in endothelial and smooth muscle cells.

Transplant vasculopathy (TV) is an accelerated form of atherosclerosis resulting in chronic rejection of vascularized allografts. The causes of TV are multifactorial and integrate at the level of the vascular wall, leading to a phenotypic switch of endothelial cells (ECs) and smooth muscle cells (SMCs). A20 is a NF-kappaB-dependent stress response gene in ECs and SMCs with potent anti-inflammatory effect in both cell types through blockade of NF-kappaB. A20 expression in ECs and SMCs correlates with the absence of TV in rat kidney allografts and long-term functioning human kidney allografts. We demonstrate that A20 protects ECs from tumor necrosis factor, Fas, and natural killer cell-mediated apoptosis by inhibiting proteolytic cleavage of caspase 8. A20 also safeguards ECs from complement-mediated necrosis. Hence, effectively shutting down cell death pathways initiated by inflammatory and immune offenders associated with TV. In contrast, A20 sensitizes SMCs to cytokine and Fas-mediated apoptosis through a novel nitric oxide (NO)-dependent mechanism. The unexpected proapoptotic effect of A20 in SMCs translates in vivo by the regression of established neointimal carotid lesions following balloon angioplasty in rats. Antedating apoptosis of SMCs, expression of the inducible NO synthase increases in A20-expressing neointimal SMCs, corroborating the involvement of NO in causing the proapoptotic effect of A20 in SMCs. Combined anti-inflammatory and anti- or proapoptotic functions of A20 in ECs and SMCs respectively qualify the positive effect of A20 upon vascular remodeling and healing. We propose that A20-based therapies may be effective in prevention and treatment of TV.

Animals↗
PubMed2025

When glycobiology meets inflammasome activation: Insights and implications.

BACKGROUND: Glycobiology focuses mainly on the study of glycan structures and their biological functions. Glycans not only provide a basic energy supply through the tricarboxylic acid cycle and glycolysis but also serve as important immune regulators during pathogen invasion and homeostasis maintenance. Inflammasomes are critical multiprotein complexes of the immune system that detect both exogenous pathogenic threats and endogenous danger signals to mediate inflammatory responses. Glycobiology has revealed significant insights into the mechanisms of immune responses, particularly in the context of inflammasome activation. AIM OF REVIEW: This review summarizes the multifaceted relationships between glycobiology and inflammasome activation, highlighting how glycan structures, glycosylation patterns, and glycan-binding proteins influence inflammasome pathways. This review sheds light on novel targets for drug development aimed at modulating inflammatory pathways through the targeting of specific glycan structures. KEY SCIENTIFIC CONCEPTS OF REVIEW: Glycans directly or indirectly provide prime and activation signals for inflammasomes, glycosylation of inflammasome-related proteins by glycan structures modulates inflammasome activation and downstream inflammation, and the interaction between glycans and lectins also provides regulatory signals for inflammasome activation. This intersection of glycobiology and inflammasome activation presents a unique opportunity to elucidate the molecular mechanisms underlying inflammatory responses and their potential therapeutic implications.

Inflammasomes↗
PubMed2003

Depression in cancer: new developments regarding diagnosis and treatment.

Considerable data demonstrate the high prevalence of symptoms of depression in patients with a wide variety of neoplastic disorders. Moreover, the dire consequences of these depressive symptoms in cancer patients have been well documented. Recent conceptual developments in the potential contributing mechanisms include increasing appreciation of the possibility that behavioral alterations in cancer patients may represent a "sickness syndrome" that results from activation of the inflammatory cytokine network. This sickness syndrome, which has been well documented in patients and laboratory animals exposed to inflammatory cytokines, includes symptoms that overlap with those seen in major depression. Conceptualizing these symptoms as components of cytokine-mediated sickness behavior has several important, and potentially novel, implications, including 1) an expansion of the neurobehavioral symptoms that are relevant to diagnosis and treatment; and 2) an increased appreciation of the potential diagnostic utility of peripheral markers of inflammation, as well as cytokine-related neurocircuitry alterations as defined by brain imaging. Treatment implications focus on the pathways by which inflammatory cytokines influence behavior, including therapeutic targets such as the inflammatory cytokines themselves, corticotropin-releasing hormone, and monoaminergic neurotransmitters and their precursors. Finally, recent data suggest that aggressive treatment strategies initiated before inflammation-inducing cancer treatments might prevent behavioral alterations, including depression, before they occur.

Antidepressive Agents↗
PubMed2006

The effects of cardamonin on lipopolysaccharide-induced inflammatory protein production and MAP kinase and NFkappaB signalling pathways in monocytes/macrophages.

BACKGROUND AND PURPOSE: In this study we examined the effect of the natural product cardamonin, upon lipopolysaccharide (LPS)-induced inflammatory gene expression in order to attempt to pinpoint the mechanism of action. EXPERIMENTAL APPROACHES: Cardamonin was isolated from the Greek plant A. absinthium L. Its effects were assessed on LPS-induced nitrite release and iNOS and COX-2 protein expression in two macrophage cell lines. Western blotting was used to investigate its effects on phosphorylation of the mitogen activated protein (MAP) kinases, ERK, JNK and p38 MAP kinase, and activation of the NFkappaB pathway, at the level of IkappaBalpha degradation and phosphorylation of NFkappaB. Also its effects on NFkappaB and GAS/GAF-DNA binding were assessed by EMSA. KEY RESULTS: Cardamonin concentration-dependently inhibited both NO release and iNOS expression but had no effect on COX-2 expression. It did not affect phosphorylation of the MAP kinases, degradation of IkappaBalpha or phosphorylation of NFkappaB. However, it inhibited NFkappaB DNA-binding in both LPS-stimulated cells and nuclear extracts of the cells (in vitro). It also inhibited IFNgamma-stimulated iNOS induction and GAS/GAF-DNA binding. CONCLUSIONS AND IMPLICATIONS: These results show that the inhibitory effect of cardamonin on LPS-induced iNOS induction is not mediated via effects on the initial activation of the NFkappaB or MAP kinase pathways but is due to a direct effect on transcription factor binding to DNA. However, although some selectivity in cardamonin's action is implicated by its inability to affect COX-2 expression, its exact mechanism(s) of action has yet to be identified.

Animals↗
PubMed2005

Novel signal transduction modulators for the treatment of airway diseases.

Multiple signal transduction pathways are involved in the inflammatory process in the airways of patients with asthma and chronic obstructive pulmonary disease (COPD), hence modulators of these pathways may result in novel anti-inflammatory treatments. The advantage of this approach is that these pathways are activated in many inflammatory and structural cells of the airways, hence a broad spectrum of anti-inflammatory effects may be possible. However, this also makes it more likely that side effects may be limiting, but this may not be a problem if the signal transduction pathway is selectively activated in disease and the therapeutic index may be increased by inhaled delivery. Phosphodiesterase-4 (PDE4) inhibitors are the most advanced treatment in this category as anti-inflammatory treatment for asthma and COPD, although side effects are dose limiting. Other promising approaches are inhibitors of p38 mitogen-activated protein (MAP) kinase, inhibitor of nuclear factor-kappaB kinase-2 (IKK2), and Syk kinase, all of which are in clinical development. Several other kinases and transcription factors are also targets for novel drug development. It is likely that modulators of signal transduction pathways may lead to the development of several novel anti-inflammatory treatments for asthma and COPD in the future.

Adrenal Cortex Hormones↗
PubMed2005

The Rho-kinase pathway regulates angiotensin II-induced renal damage.

BACKGROUND: Angiotensin II (AngII) is a key factor in the pathogenesis of renal damage. AngII via AngII type 1 receptors activates several intracellular signaling systems, including the small guanosine triphosphatase Rho and its downstream effector Rho-dependent serine-threonine kinase (Rho-kinase). The Rho/Rho-kinase pathway contributes to inflammatory and proliferative changes observed in cardiovascular diseases. However, the data on renal diseases are scarce. The aim of this study was to investigate the effect of Rho-kinase inhibition in AngII-induced renal damage. METHODS: We used the model of systemic AngII infusion into normal rats (100 ng/kg per minute; subcutaneous osmotic minipumps), and some animals were treated with the Rho-kinase inhibitor Y-27632 (30 mg/kg per day). In the kidneys of these animals, we evaluated renal lesions, transcription factor activity (by electrophoretic mobility shift assay), and messenger RNA (by polymerase chain reaction) and protein expression levels (by Western blot and/or immunohistochemistry) of proinflammatory and profibrotic factors. RESULTS: Rats infused with AngII for three days present renal inflammatory cell infiltration and slight tubular damage, which were diminished by treatment with the Rho-kinase inhibitor Y-27632. AngII activates nuclear factor-kappaB and causes overexpression of proinflammatory factors, including cytokines (tumor necrosis factor alpha) and chemokines (monocyte chemotactic protein-1), and of profibrotic factors (connective tissue growth factor). Treatment of AngII-infused rats with Y-27632 decreases the upregulation of these proinflammatory and profibrotic mediators. CONCLUSION: These data demonstrate that the Rho-kinase pathway is involved in renal damage caused by AngII through the regulation of proinflammatory and profibrotic mediators. These results suggest that inhibition of the Rho-kinase pathway represents a novel therapy for renal diseases associated with local AngII generation.

Amides↗
PubMed2006

Tumor necrosis factor-alpha activates signal transduction in hypothalamus and modulates the expression of pro-inflammatory proteins and orexigenic/anorexigenic neurotransmitters.

Tumor necrosis factor-alpha (TNF-alpha) is known to participate in the wastage syndrome that accompanies cancer and severe infectious diseases. More recently, a role for TNF-alpha in the pathogenesis of type 2 diabetes mellitus and obesity has been shown. Much of the regulatory action exerted by TNF-alpha upon the control of energy stores depends on its action on the hypothalamus. In this study, we show that TNF-alpha activates canonical pro-inflammatory signal transduction pathways in the hypothalamus of rats. These signaling events lead to the transcriptional activation of an early responsive gene and to the induction of expression of cytokines and a cytokine responsive protein such as interleukin-1beta, interleukin-6, interleukin-10 and suppressor of cytokine signalling-3, respectively. In addition, TNF-alpha induces the expression of neurotransmitters involved in the control of feeding and thermogenesis. Thus, TNF-alpha may act directly in the hypothalamus inducing a pro-inflammatory response and the modulation of expression of neurotransmitters involved in energy homeostasis.

Animals↗
PubMed2003

Hemoglobin scavenger receptor CD163 mediates interleukin-10 release and heme oxygenase-1 synthesis: antiinflammatory monocyte-macrophage responses in vitro, in resolving skin blisters in vivo, and after cardiopulmonary bypass surgery.

The recently described hemoglobin scavenger receptor CD163 mediates the endocytosis of hemoglobin:haptoglobin (Hb:Hp) complexes and thereby counters Hb-induced oxidative tissue damage after hemolysis. Although CD163 has been indirectly associated with antiinflammatory and atheroprotective activity, no ligand-receptor-effector pathway has yet been described for this receptor. To understand the significance of CD163 and more clearly define downstream pathways linked to inflammatory resolution, we studied the expression and function of CD163 in human monocytes/macrophages using both in vitro and in vivo models. Differentiation of human blood monocytes into macrophages either by in vitro culture or in resolving cantharidin-induced skin blisters led to an equivalent increase (>15x) in CD163 expression. Elevated CD163 levels were also noted on circulating monocytes in cardiac surgical patients during the resolution phase of the systemic inflammatory response to cardiopulmonary bypass surgery. In each case, binding of Hb:Hp to CD163-bearing cells elicited potent interleukin-10 secretion, and this was inhibited by the anti-CD163 antibody RM3/1. Release of interleukin-10, in turn, induced heme oxygenase-1 stress protein synthesis via an autocrine mechanism. Such induction of heme oxygenase-1 was observed in vivo 24 to 48 hours after the onset of cardiopulmonary bypass surgery. These results identify novel antiinflammatory and cytoprotective effector pathways in human monocytes/macrophages related to Hb scavenging and metabolism, which may have relevance in atheroprotection, wound healing, and patient recovery postoperatively.

Aged↗