Biomedical subjects

Jörg Köhl

Publications and source records attributed to Jörg Köhl.

18 recordsLinked to original sources

PubMed2006

Complement regulates inhalation tolerance at the dendritic cell/T cell interface.

Pulmonary exposure to innocuous aeroallergens is a common event leading to inhalation tolerance. Distinct subsets of pulmonary dendritic cells (DC) and regulatory T cells (T(Reg)) play critical roles in mediating and maintaining such tolerance. In asthmatics, the same aeroallergens drive a maladaptive, Th2-biased immune response resulting in airway inflammation and airway hyper-reactivity. The mechanisms underlying the breakdown of inhalation tolerance, leading to the Th2-driven inflammation in rising numbers of asthmatic patients from industrialized countries remain elusive. The recent resurgence of interest in the role of the innate immune mediators in regulating adaptive immune response has sparked studies aimed at identifying the role of complement in allergic asthma. In this context, an unexpected role for the anaphylatoxin C5a receptor in allergic sensitization has been found. In models of experimental allergic asthma, ablation of C5aR signaling during initial allergen exposure either induced or enhanced Th2 sensitization. Mechanistically, C5aR signaling directly affected the function of distinct pulmonary DC subsets that induce or control allergen-induced adaptive immune responses. Signaling pathways downstream of C5 may also impact the function of T(Reg), as T(Reg) from C5 sufficient, but not from C5 deficient mice, suppress DC activation and subsequent development of Th2-driven inflammation. The emerging paradigm is that constitutive local generation of C5a and C5aR signaling in airway DCs controls inhalation tolerance directly as well as indirectly through sensitization of airway DCs for T(Reg)-mediated immunosuppression.

Allergens↗

PubMed2006

Self, non-self, and danger: a complementary view.

Complement is a sophisticated system of molecules that is critical to the functional integrity of the body. Initially considered as a defense system to ward off infections, it becomes increasingly clear that the complement system is one of the most important humoral systems to sense danger, i.e., to recognize conserved patterns on pathogens and on altered/damaged self. In addition to this important role in danger recognition, the complement system has the ability to translate the danger information into an adequate cellular innate or adaptive immune response. This is accomplished by two distinct mechanisms: (a) danger sensors that have recognized altered cells or pathogens can directly activate cell-bound receptors (e.g., C1q/C1q receptor interaction), and/or (b) danger sensors initiate cleavage of complement factors C3 and C5, the fragments of which acquire the ability to bind to complement receptors and/or regulators. It is the specific interaction of the danger sensors and of the cleavage fragments with distinct cell-bound receptors/regulators that directs the immune response toward an innate or an adaptive phenotype. Further, the expression pattern of the complement receptors critically impacts the shape of the immune response. Complement has the ability to discriminate between physiological and pathological danger, i.e., physiological cell death and death in response to injury. In the former case, cells are merely flagged for enhanced phagocytosis (by C3 fragments) without accompanying inflammation (through CR3), whereas in the latter case inflammatory signals are accessorily triggered (e.g., by the release of ATs, which recruit and activate neutrophils, eosinophils, etc.). This function is of major importance for apoptotic cell clearance and tissue repair but plays also important roles in fibrotic tissue remodeling in response to chronic tissue injury. Further, complement cleavage fragments may prevent the development of maldaptive immune responses at the mucosal surface. Here, complement fragment C5a does not act as a danger transmitter but as a "homeostasis transmitter," as its interaction with the C5a receptor on DCs provides a signal that prevents DCs from activating CD4+ T cells. The generation of regulatory T cells in response to CD46 ligation may have a similar function, as injured cells lose CD46 expresssion, which may lead to decreased proliferation of Tregs and, consecutively, increased production of T effector cells. Although we are still at the beginning of understanding the complex interaction patterns within the complement system, recent data suggest substantial crosstalk between the signaling pathways downstream of complement receptors and other receptors of the innate immune system that function as immune sensors and/or transmitters (i.e., TLRs, FcgammaRs130,131). Given the importance of complement as a sensor and effector system of innate and adaptive immune responses, a complement-related view of the immune system might help to unravel some enigmas of autoimmunity, allergy, and transplantation.

Anaphylatoxins↗

PubMed2006

Complement and Toll-like receptors: key regulators of adaptive immune responses.

The innate immune system provides sophisticated defense mechanisms to protect complex macroorganisms from the attack of microorganisms. Among those, the complement system and Toll-like receptors are of paramount importance to discriminate between infectious non-self and non-infectious self and to provide critical danger signals instructing adaptive immune responses. Here, we will discuss recent advances in our understanding of the mechanisms underlying complement and TLR-mediated regulation of adaptive immunity. We will focus on the regulation of T cell immunity and discuss recent findings on the cross-talk between complement receptor and TLR signaling pathways. Such cross-talk is likely to affect the outcome of infections with intracellular pathogens, as well as the initiation and maintenance of aberrant immune responses leading to autoimmunity and atopy.

Animals↗

PubMed2006

A regulatory role for the C5a anaphylatoxin in type 2 immunity in asthma.

Complement component 5 (C5) has been described as either promoting or protecting against airway hyperresponsiveness (AHR) in experimental allergic asthma, suggesting pleomorphic effects of C5. Here we report that local pharmacological targeting of the C5a receptor (C5aR) prior to initial allergen sensitization in murine models of inhalation tolerance or allergic asthma resulted in either induction or marked enhancement of Th2-polarized immune responses, airway inflammation, and AHR. Importantly, C5aR-deficient mice exhibited a similar, increased allergic phenotype. Pulmonary allergen exposure in C5aR-targeted mice resulted in increased sensitization and accumulation of CD4+ CD69+ T cells associated with a marked increase in pulmonary myeloid, but not plasmacytoid, DC numbers. Pulmonary DCs from C5aR-targeted mice produced large amounts of CC chemokine ligand 17 (CCL17) and CCL22 ex vivo, suggesting a negative impact of C5aR signaling on pulmonary homing of Th2 cells. In contrast, C5aR targeting in sensitized mice led to suppressed airway inflammation and AHR but was still associated with enhanced production of Th2 effector cytokines. These data suggest a dual role for C5a in allergic asthma, i.e., protection from the development of maladaptive type 2 immune responses during allergen sensitization at the DC/T cell interface but enhancement of airway inflammation and AHR in an established inflammatory environment.

Allergens↗

PubMed2006

The role of complement in danger sensing and transmission.

Self-non-self discrimination has long been considered the main function of the immune system. Increasing evidence supports the view of the immune system as a network of complex danger sensors and transmitters in which self-non-self discrimination is only one facet. To meet the challenge of danger sensing, the immune system carries a large stock of germline-encoded, highly conserved molecules that can recognize microbial as well as modified host structures. Among those are the Toll-like receptors (TLR), which comprise a dozen membrane-bound pattern-recognition receptors that directly link danger recognition to danger transmission through activation of several distinct cellular signaling pathways. Here, I discuss the function and biology of a complex, evolutionary ancient system, the complement system, which has long been considered critical to host defense. In contrast to TLRs, the complement system senses danger by a panel of soluble molecules that can directly bind to specific complement receptors and/or initiate a complex cascade of proteolytic events that lead to the generation of soluble complement fragments able to bind to another, distinct set of specific complement receptors. As I will outline in this review, complement- mediated danger sensing and the complex transition of this information into distinct cellular activation profiles is critical for tissue homeostasis under steady-state conditions and in response to infection and cell injury. Furthermore, I will discuss recent findings that support a concept of intense cross-talk between the complement system and TLRs, which defines the quality and the magnitude of immune responses in vivo.

Animals↗

PubMed2005

CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function.

The role of natural CD4+CD25+ regulatory T (T reg) cells in the control of allergic asthma remains poorly understood. We explore the impact of T reg cell depletion on the allergic response in mice susceptible (A/J) or comparatively resistant (C3H) to the development of allergen-induced airway hyperresponsiveness (AHR). In C3H mice, anti-CD25-mediated T reg cell depletion before house dust mite treatment increased several features of the allergic diathesis (AHR, eosinophilia, and IgE), which was concomitant with elevated T helper type 2 (Th2) cytokine production. In similarly T reg cell-depleted A/J mice, we observed a moderate increase in airway eosinophilia but no effects on AHR, IgE levels, or Th2 cytokine synthesis. As our experiments suggested that T reg cell depletion in C3H mice before sensitization was sufficient to enhance the allergic phenotype, we characterized dendritic cells (DCs) in T reg cell-depleted C3H mice. T reg cell-depleted mice had increased numbers of pulmonary myeloid DCs with elevated expression of major histocompatibility complex class II, CD80, and CD86. Moreover, DCs from T reg cell-depleted mice demonstrated an increased capacity to stimulate T cell proliferation and Th2 cytokine production, which was concomitant with reduced IL-12 expression. These data suggest that resistance to allergen-driven AHR is mediated in part by CD4+CD25+ T reg cell suppression of DC activation and that the absence of this regulatory pathway contributes to susceptibility.

Animals↗

PubMed2005

Opposing regulatory roles of complement factor 5 in the development of bleomycin-induced pulmonary fibrosis.

The mechanisms of idiopathic pulmonary fibrosis pathogenesis, a chronic and progressive interstitial lung disease, remain elusive. The complement system, a crucial arm of the innate immune response, plays a pivotal role in several pathological disorders; however, the contribution of individual complement components to lung fibrosis has not yet been examined. Complement factor 5 (C5) and its cleavage product C5a are critical mediators in inflammatory diseases. Thus, to evaluate the role of C5 in lung fibrosis, we compared congenic C5-sufficient and C5-deficient mice in a well-characterized murine model of bleomycin-induced pulmonary fibrosis. C5-deficient mice had an exaggerated inflammatory phenotype compared with C5-sufficient mice during acute bleomycin-induced lung injury. These findings suggest a protective and anti-inflammatory role for C5, which was linked to the regulation of matrix metalloproteinases involved in cell migration. In contrast, C5 had a detrimental effect during chronic stages of bleomycin-induced injury, indicating a profibrotic role for C5. This deleterious activity for C5 was associated with expression of the fibrogenic cytokine TGF-beta1 and matrix metalloproteinase-3, an important mediator in fibroblast contraction. Altogether, our data reveal novel and opposing roles for C5 in both inflammation and tissue repair. Furthermore, these findings provide insight into the development of new therapeutic strategies for idiopathic pulmonary fibrosis patients.

Animals↗

PubMed2005

Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans.

Fibrogenesis or scarring of the liver is a common consequence of all chronic liver diseases. Here we refine a quantitative trait locus that confers susceptibility to hepatic fibrosis by in silico mapping and show, using congenic mice and transgenesis with recombined artificial chromosomes, that the gene Hc (encoding complement factor C5) underlies this locus. Small molecule inhibitors of the C5a receptor had antifibrotic effects in vivo, and common haplotype-tagging polymorphisms of the human gene C5 were associated with advanced fibrosis in chronic hepatitis C virus infection. Thus, the mouse quantitative trait gene led to the identification of an unknown gene underlying human susceptibility to liver fibrosis, supporting the idea that C5 has a causal role in fibrogenesis across species.

Animals↗

PubMed2005

Macrophages induce the inflammatory response in the pulmonary Arthus reaction through G alpha i2 activation that controls C5aR and Fc receptor cooperation.

Complement and FcgammaR effector pathways are central triggers of immune inflammation; however, the exact mechanisms for their cooperation with effector cells and their nature remain elusive. In this study we show that in the lung Arthus reaction, the initial contact between immune complexes and alveolar macrophages (AM) results in plasma complement-independent C5a production that causes decreased levels of inhibitory FcgammaRIIB, increased levels of activating FcgammaRIII, and highly induced FcgammaR-mediated TNF-alpha and CXCR2 ligand production. Blockade of C5aR completely reversed such changes. Strikingly, studies of pertussis toxin inhibition show the essential role of G(i)-type G protein signaling in C5aR-mediated control of the regulatory FcgammaR system in vitro, and analysis of the various C5aR-, FcgammaR-, and G(i)-deficient mice verifies the importance of Galpha(i2)-associated C5aR and the FcgammaRIII-FcgammaRIIB receptor pair in lung inflammation in vivo. Moreover, adoptive transfer experiments of C5aR- and FcgammaRIII-positive cells into C5aR- and FcgammaRIII-deficient mice establish AM as responsible effector cells. AM lacking either C5aR or FcgammaRIII do not possess any such inducibility of immune complex disease, whereas reconstitution with FcgammaRIIB-negative AM results in an enhanced pathology. These data suggest that AM function as a cellular link of C5a production and C5aR activation that uses a Galpha(i2)-dependent signal for modulating the two opposing FcgammaR, FcgammaRIIB and FcgammaRIII, in the initiation of the inflammatory cascade in the lung Arthus reaction.

Animals↗

PubMed2005

Pharmacological targeting of anaphylatoxin receptors during the effector phase of allergic asthma suppresses airway hyperresponsiveness and airway inflammation.

Airway hyperresponsiveness and airway inflammation are hallmarks of allergic asthma, the etiology of which is crucially linked to the presence of Th2 cytokines. A role for the complement anaphylatoxins C3a and C5a in allergic asthma was suggested, as deficiencies of the C3a receptor (C3aR) and of complement factor C5 modulate airway hyperresponsiveness, airway inflammation, and Th2 cytokine levels. However, such models do not allow differentiation of effects on the sensitization phase and the effector phase of the allergic response, respectively. In this study, we determined the role of the anaphylatoxins on the effector phase of asthma by pharmacological targeting of the anaphylatoxin receptors. C3aR and C5a receptor (C5aR) signaling was blocked using the nonpeptidic C3aR antagonist SB290157 and the neutralizing C5aR mAb 20/70 in a murine model of Aspergillus fumigatus extract induced pulmonary allergy. Airway hyperresponsiveness was substantially improved after C5aR blockade but not after C3aR blockade. Airway inflammation was significantly reduced in mice treated with the C3aR antagonist or the anti-C5aR mAb, as demonstrated by reduced numbers of neutrophils and eosinophils in bronchoalveolar lavage fluid. Of note, C5aR but not C3aR inhibition reduced lymphocyte numbers in bronchoalveolar lavage fluid. Cytokine levels of IL-5 and IL-13 in bronchoalveolar lavage fluid were not altered by C3aR or C5aR blockade. However, blockade of both anaphylatoxin receptors markedly reduced IL-4 levels. These data suggest an important and exclusive role for C5aR signaling on the development of airway hyperresponsiveness during pulmonary allergen challenge, whereas both anaphylatoxins contribute to airway inflammation and IL-4 production.

Animals↗

PubMed2005

C5a negatively regulates toll-like receptor 4-induced immune responses.

The complement system and the Toll-like receptors (TLRs) are two central arms of innate immunity that are critical to host defense as well as the development of adaptive immunity. Most pathogens activate both complement and TLRs, suggesting the potential for crosstalk between the two systems. We show here that the complement-derived C5a anaphylatoxin negatively regulates TLR4- and CD40-induced synthesis of IL-12 family cytokines (IL-12, IL-23, and IL-27) from inflammatory macrophages (M phi s) by extracellular signal-regulated kinase- and phosphoinositide 3 kinase-dependent pathways. This decreased cytokine response translates into a decreased T helper type 1 (Th1) response in vitro and in vivo. Accordingly, we found enhanced Th1 immunity in C5a receptor-deficient mice, something that conferred protection from Leishmania major infection. Our findings identify the negative impact of C5a on IL-12 family cytokines as an important mechanism for regulating Th1 polarization in response to innate and adaptive immune network activation.

Animals↗

PubMed2004

C5a initiates the inflammatory cascade in immune complex peritonitis.

Immune complex (IC)-induced inflammation is integral to the pathogenesis of several autoimmune diseases. ICs activate the complement system and interact with IgG FcgammaR. In this study, we demonstrate that activation of the complement system, specifically generation of C5a, initiates the neutrophilic inflammation in IC peritonitis. We show that ablation of C5a receptor signaling abrogates neutrophil recruitment in wild-type mice and prevents the enhancement of neutrophil migration seen in FcgammaRIIB(-/-) mice, suggesting that C5aR signaling is the crucial initial event upstream of FcgammaR signaling. We also provide evidence that C5a initiates the inflammatory cascade both directly, through C5aR-mediated effector functions on infiltrating and resident peritoneal cells, and indirectly, through shifting the balance between activating and inhibitory FcgammaRs on resident cells toward an inflammatory phenotype. We conclude that complement activation and C5a generation are prerequisites for IC-induced inflammation through activating FcgammaR, which amplifies complement-induced inflammation in autoimmunity.

Animals↗

PubMed2004

The anaphylatoxins bridge innate and adaptive immune responses in allergic asthma.

The complement system has long been recognized for its role as a lytic effector system that protects against microbial pathogens, as well as for its role in mediating acute and chronic inflammatory responses. Many of the inflammatory sequelae of complement activation can be related to the complement cleavage fragments C3a and C5a, the so-called anaphylatoxins (ATs). Cloning and subsequent gene targeting of their corresponding receptors, as well as generation of specific C3a and C5a inhibitors, have fueled new interest in studies aimed at defining the roles of the anaphylatoxins in inflammatory diseases. Traditionally, the anaphylatoxins have been considered mediators of end-stage effector mechanisms. However, recent data from animal models of allergic asthma suggest that C3a and C5a provide a critical link between innate and adaptive immunity. This review is aimed at outlining our current knowledge of when and where anaphylatoxins contribute to and control the development of allergic asthma. The accumulated data suggest a model in which C3a and C5a play important but opposing roles during allergen-induced T-cell polarization: C3a promotes Th2 responses, whereas C5a prevents Th2 polarization. During the effector phase, both anaphylatoxins trigger the inflammatory response and contribute to bronchoconstriction.

Allergens↗

PubMed2003

C5a mutants are potent antagonists of the C5a receptor (CD88) and of C5L2: position 69 is the locus that determines agonism or antagonism.

The anaphylatoxin C5a exerts a plethora of biologic activities critical in the pathogenesis of systemic inflammatory diseases. Recently, we reported on a C5a mutant, jun/fos-A8, as a potent antagonist for the human and mouse C5a receptor (CD88). Addressing the molecular mechanism accounting for CD88 receptor antagonism by site-directed mutagenesis, we found that a positively charged amino acid at position 69 is crucial. Replacements by either hydrophobic or negatively charged amino acids switched the CD88 antagonist jun/fos-A8 to a CD88 agonist. In addition to CD88, the seven-transmembrane receptor C5L2 has recently been found to provide high affinity binding sites for C5a and its desarginated form, C5adesArg74. A jun/fos-A8 mutant in which the jun/ fos moieties and amino acids at positions 71-73 were deleted, A8Delta71-73, blocked C5a and C5adesArg74 binding to CD88 and C5L2. In contrast, the cyclic C5a C-terminal analog peptide AcF-[OP-d-ChaWR] inhibited binding of the two anaphylatoxins to CD88 but not to C5L2, suggesting that the C5a core segment is important for high affinity binding to C5L2. Both receptors are coexpressed on human monocytes and the human mast cell line HMC-1; however, C5L2 expression on monocytes is weaker as compared with HMC-1 cells and highly variable. In contrast, no C5L2 expression was found on human neutrophils. A8Delta71-73 is the first antagonist that blocks C5a and C5adesArg74 binding to both C5a receptors, CD88 and C5L2, making it a valuable tool for studying C5L2 functions and for blocking the biological activities of C5a and C5adesArg74 in mice and humans.

Amino Acid Sequence↗

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↗

PubMed2003

IL-4 down-regulates anaphylatoxin receptors in monocytes and dendritic cells and impairs anaphylatoxin-induced migration in vivo.

Anaphylatoxins mobilize leukocytes to the sites of inflammation. In the present study we investigated the impact of GM-CSF, IL-4, and IFN-gamma on anaphylatoxin receptor expression in monocytes and dendritic cells (DC). IL-4 was identified as the strongest down-regulator of the receptors for C5a and C3a in monocytes and monocyte-derived DC (MoDC). To study the impact of IL-4 on anaphylatoxin-induced chemotaxis, an in vivo migration model was established. For this purpose, human monocytes and MoDC were injected i.v. into SCID mice that at the same time received anaphylatoxins into the peritoneal cavity. A peritoneal influx of human monocytes could be demonstrated by 4 h after injections of C5a and C3a. In line with receptor down-regulation, IL-4 treatment inhibited in vivo mobilization of human monocytes and MoDC in response to C5a and C3a. In addition to its effects on human cells, IL-4 reduced C5a receptors in murine bone marrow-derived DC and impaired recruitment of labeled bone marrow-derived DC in syngeneic BALB/c mice to i.p. injected C5a. Overall, these data suggest that inhibition of a rapid anaphylatoxin-induced mobilization of monocytes and DC to inflamed tissues represents an important anti-inflammatory activity of the Th2 cytokine IL-4.

Anaphylaxis↗

PubMed2003

Structure-function studies of the C3a-receptor: C-terminal serine and threonine residues which influence receptor internalization and signaling.

The anaphylatoxic peptide C3a is a pro-inflammatory mediator generated during complement activation, whose specific G protein coupled receptor is expressed on granulocytes, monocytes, mast cells, activated lymphocytes, and in the nervous tissue. We have generated RBL-2H3 cell clones stably expressing mutants of the human C3a-receptor (C3aR) with combined alanine (Ala) substitutions of ten C-terminal serine (Ser) or threonine (Thr) residues, which may represent putative phosphorylation sites to characterize their role in ligand-induced C3aR internalization and signaling. Ser475/479 and Thr480/481 as well as Ser449 seemed not to be involved in ligand-induced receptor internalization. Either directly or by a conformational change they even "inhibit" C3aR internalization. In contrast, mutants with Ala substitutions at Ser465/470 and Thr463/466 were poorly internalized, and Thr463 seemed to be the most important C-terminal Thr or Ser residue directly effecting receptor internalization. However, it is likely that other C3aR regions additionally participate in this negative feed-back mechanism since even mutants with multiple Ala substitutions still internalized to a limited degree. Interestingly, in a mutant with a single exchange of Ser449 to Ala, the signal transduction assessed by a Ca(2+) assay and [(35)S]GTP gamma S-binding on HEK cells transiently co-transfected with G-alpha 16 or G-alpha O, respectively, was severely impaired, indicating that this residue of C3aR is involved in G protein coupling.

Animals↗

PubMed2002

Essential role of the C5a receptor in E coli-induced oxidative burst and phagocytosis revealed by a novel lepirudin-based human whole blood model of inflammation.

Complement plays an essential role in inflammation and tissue damage. However, it is largely unknown to what extent the system acts as a primary inducer of secondary mediator systems in the inflammatory network of human whole blood. Here we describe a novel in vitro model using the thrombin-specific hirudin analog lepirudin as anticoagulant, which, in contrast to heparin, did not interfere with complement activation. The model was used to study the role of complement in Escherichia coli-induced inflammatory responses. Granulocyte and monocyte oxidative burst was complement dependent as it was reduced by 85% and 70%, respectively, by the C3 [corrected] binding peptide compstatin. A similar reduction was found by inhibition of C5, C5a, and C5a receptor (C5aR). Furthermore, anti-CR3 antibodies were as efficient as the C5aR antagonist in reducing granulocyte oxidative burst, whereas blocking CD14 or C3aR had no effect. Up-regulation of granulocyte CR3 was virtually abolished by a C5aR antagonist. Opsonization and phagocytosis was completely inhibited by blocking of C5aR or CR3, whereas blocking of the FcgammaRs (CD16, CD32, CD64) had no effect. In contrast to oxidative burst and phagocytosis, cytokine secretion was largely complement independent. Thus, anti-CD14 abolished tumor necrosis factor-alpha, interleukin-6 (IL-6), and IL-10 secretion, whereas IL-8 was equally inhibited by anti-CD14 and compstatin. In conclusion, the present model is particularly useful for studying complement as part of the inflammatory network. The results emphasize a crucial role for C5a-C5aR interaction in E coli-induced up-regulation of CR3 and the subsequent oxidative burst and phagocytosis. Complement inhibition may have therapeutic implications in oxidative burst-induced tissue damage.

Antigens, CD↗