Modulation Of Chemokines Research Articles

The transcriptional response to lipopolysaccharide reveals a role for interferon-γ in lung neutrophil recruitment

Neutrophil recruitment to the lung after lipopolysaccharide (LPS; endotoxin) inhalation is primarily dependent on Toll-like receptor 4 (Tlr4) signaling, because it is virtually absent in mice deficient in Tlr4. However, among strains wild type for Tlr4, the magnitude of neutrophil recruitment to the lung after LPS inhalation is variable, suggesting the involvement of genes other than Tlr4. To identify genes associated with the inflammatory response to inhaled LPS, we evaluated the transcriptional response in lungs of 12 inbred strains of mice, 8 which are wild type for Tlr4 and 4 of which lack functional Tlr4. Using the promoter integration in microarray analysis algorithm, we scanned our gene list for transcription factor-binding sites significantly overrepresented among Tlr4 wild-type strains with high neutrophil influx in the lung after LPS inhalation. This analysis identified the interferon (IFN)-stimulated response element (ISRE) as the most overrepresented transcription factor (present in 24% of the promoters) associated with the neutrophil influx to the lower respiratory tract. To test the validity of this observation, we evaluated IFN-gamma-deficient mice and found that the presence of IFN-gamma is essential for robust neutrophil recruitment to the lower respiratory tract and modulation of key regulatory cytokines and chemokines after LPS inhalation. In conclusion, using a genomic approach, we identified the ISRE as a transcriptional element associated with the neutrophil response to inhaled LPS and demonstrated for the first time that IFN-gamma plays a critical role in LPS-induced neutrophil recruitment to the lower airways.

Chemokine receptor expression and modulation by Mycobacterium tuberculosis antigens on mononuclear cells from human lymphoid tissues

Chemokine receptor switching on lymphoid cells is an important factor regulating migration and homing, but little is known about the expression of such molecules during Mycobacterium tuberculosis infection in humans. We describe CCR2, CCR5 and CCR7 expression on human cells from blood, spleen and pulmonary hilar lymph nodes (PHLN) stimulated by M. tuberculosis antigens. CCR2 was not expressed by CD3+ cells regardless of the presence of antigen, but was highly expressed on CD14+ CD63+ monocytes/macrophages. CCR2 decreased on splenic monocytes/macrophages by nearly 50% in culture, independent of antigen, but remained high in blood and PHLN. CCR5 was low in CD3+ cells and was down-regulated by M. tuberculosis antigens on blood and splenic cells but not in PHLN. CCR5 was highly expressed on monocytes/macrophages and was down-regulated by M. tuberculosis antigens at 48 hr only in blood. Less than 15% of CD3+ cells from spleen and PHLN were CCR7+, whereas nearly 40% from blood expressed this receptor on primary isolation. However, CCR7 in PHLN increased in culture, independent of antigen. Monocytes/macrophages did not express CCR7. Thus, we characterize, for the first time, chemokine receptor expression and differential modulation by M. tuberculosis antigens on human mononuclear cells from spleen, blood and PHLN. Knowledge of chemokine receptor switching in human lymphoid tissue provides novel insight into mechanisms of the immune response to M. tuberculosis with potential effects on directing cell trafficking.

Induction of RANTES and CCR5 through NF-κB Activation via MAPK Pathway in Aged Rat Gingival Tissues

Chemokine and chemokine receptor expression in gingival tissues plays a central role in periodontal disease during aging. In the present study, we explored the modulation of chemokines and chemokine receptors expression in aging rat gingival tissues. In the 24-month-old (Old) rat gingival tissues, RANTES and CCR5 mRNA and protein levels were 2-4 fold increased over those of the 6-month-old (Young) rats. The Old rats had considerable enhancement of all three of the studied MAPK activities: extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. These results suggest that age-related increases in RANTES and CCR5 expression are associated with increased IkappaBalpha, nuclear NF-kappaB, and MAPK activity in gingival tissues.

Cannabinoid receptors in microglia of the central nervous system: immune functional relevance

Microglia, resident macrophages of the brain, function as immune effector and accessory cells. Paradoxically, they not only play a role in host defense and tissue repair but also have been implicated in a variety of neuropathological processes. Microglia, in addition to exhibiting phenotypic markers for macrophages, express CB1 and CB2 cannabinoid receptors. Recent studies suggest the existence of a third, yet-to-be cloned, non-CB1, non-CB2 cannabinoid receptor. These receptors appear to be functionally relevant within defined windows of microglial activation state and have been implicated as linked to cannabinoid modulation of chemokine and cytokine expression. The recognition that microglia express cannabinoid receptors and that their activation results in modulation of select cellular activities suggests that they may be amenable to therapeutic manipulation for ablating untoward inflammatory responses in the central nervous system.

Mobilization of Human Lymphoid Progenitors after Treatment with Granulocyte Colony-Stimulating Factor

Hemopoietic stem and progenitor cells ordinarily residing within bone marrow are released into the circulation following G-CSF administration. Such mobilization has a great clinical impact on hemopoietic stem cell transplantation. Underlying mechanisms are incompletely understood, but may involve G-CSF-induced modulation of chemokines, adhesion molecules, and proteolytic enzymes. We studied G-CSF-induced mobilization of CD34+ CD10+ CD19- Lin- and CD34+ CD10+ CD19+ Lin- cells (early B and pro-B cells, respectively). These mobilized lymphoid populations could differentiate only into B/NK cells or B cells equivalent to their marrow counterparts. Mobilized lymphoid progenitors expressed lymphoid- but not myeloid-related genes including the G-CSF receptor gene, and displayed the same pattern of Ig rearrangement status as their bone marrow counterparts. Decreased expression of VLA-4 and CXCR-4 on mobilized lymphoid progenitors as well as multipotent and myeloid progenitors indicated lineage-independent involvement of these molecules in G-CSF-induced mobilization. The results suggest that by acting through multiple trans-acting signals, G-CSF can mobilize not only myeloid-committed populations but a variety of resident marrow cell populations including lymphoid progenitors.

TRAIL counteracts the proadhesive activity of inflammatory cytokines in endothelial cells by down-modulating CCL8 and CXCL10 chemokine expression and release

AbstractExposure of endothelial cells to recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induced a modest (2-fold) increase of HL-60 cell adhesion as compared to TNF-α (40-fold) or interleukin 1β (IL-1β; 20-fold). However, pretreatment of endothelial cultures with TRAIL determined a significant reduction of the proadhesive activity induced by both TNF-α and IL-1β. Unexpectedly, the antiadhesive activity of TRAIL was not due to interference with the nuclear factor κB (NF-κB)-mediated up-regulation of surface intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin adhesion molecules in response to inflammatory cytokines. In searching for the molecular mechanism underlying this biologic activity of TRAIL, a cDNA microarray analysis was performed. TRAIL pretreatment variably down-modulated the mRNA steady-state levels of several TNF-α-induced chemokines, and, in particular, it abrogated the TNF-α-mediated up-regulation of CCL8 and CXCL10. Of note, the addition of optimal concentrations of recombinant CCL8 plus CXCL10 to endothelial cultures completely restored the proadhesive activity of TNF-α. Moreover, experiments performed with agonistic anti-TRAIL receptor antibodies demonstrated that both TRAIL-R1 and TRAIL-R2 contributed, although at different levels, to TRAIL-induced chemokine modulation. Taken together, our data suggest that TRAIL might play an important role in modulating leukocyte/endothelial cell adhesion by selectively down-regulating CCL8 and CXCL10 chemokines.

Immunomodulatory Activities of Small Host Defense Peptides

Recent studies have demonstrated that in addition to their antimicrobial activity, cationic host defense peptides, like the human cathelicidin LL-37, perform many activities relating to innate immunity, including the induction or modulation of chemokine and cytokine production, alteration of gene expression in host cells, and inhibition of proinflammatory responses of host cells to bacterial components such as lipopolysaccharide (LPS) in vitro and in vivo. To investigate if these properties are shared by smaller peptides, two cathelicidin peptides derived from bovine neutrophils, the 13-mer indolicidin and Bac2A, a linear 12-amino-acid derivative of bactenecin, were compared to the 37-amino-acid peptide LL-37. Indolicidin, like LL-37, inhibited LPS-induced tumor necrosis factor alpha (TNF-alpha) secretion, even when added up to an hour after the addition of Escherichia coli O111:B4 LPS to the human macrophage/monocyte-like THP-1 cell line. In contrast, Bac2A demonstrated no significant antiendotoxin activity. At low concentrations, indolicidin and LL-37 acted synergistically to suppress LPS-induced production of TNF-alpha. Indolicidin was analogous to LL-37 in its ability to induce the production of the chemokine interleukin-8 (IL-8) in a human bronchial cell line, 16HBE14o(-), but it was unable to induce production of IL-8 in THP-1 cells. In contrast, Bac2A was unable to induce IL-8 in either cell type. Conversely, Bac2A was chemotactic for THP-1 cells at concentrations between 10 and 100 mug/ml, while indolicidin and LL-37 were not chemotactic at these concentrations for THP-1 cells. This indicates that in addition to the potential for direct microbicidal activity, cationic host defense peptides may have diverse and complementary abilities to modulate the innate immune response.

Cytoprotection by interleukin-6 against liver injury induced by lipopolysaccharide

The role of interleukin (IL)-6 in inflammatory injury remains controversial. The present study elucidated the role of IL-6 in liver damage during severe inflammation induced by intraperitoneal administration of lipopolysaccharide (LPS; 1 mg/kg) using IL-6 null (-/-) mice and corresponding wild-type (WT) mice. Histological study showed that LPS treatment caused more severe liver injury with centrilobular vacuolation of hepatocytes and neutrophilic infiltration in the liver of IL-6 (-/-) mice; in contrast, neutrophilic infiltration and mild vacuolar change of hepatocytes were found in the liver of LPS-treated WT mice. Protein levels of proinflammatory molecules, such as IL-1beta, macrophage inflammatory protein-1alpha, and macrophage chemoattractant protein-1, in the livers were significantly greater in IL-6 (-/-) mice than in WT mice after LPS challenge. These results directly indicate that IL-6 is protective against liver injury induced by bacterial endotoxin, at least partly, via the modulation of proinflammatory cytokines and chemokines.

Pharmacological and Clinical Basis of Treatment of Familial Mediterranean Fever (FMF) with Colchicine or Analogues: An Update

Familial Mediterranean Fever (FMF), an autosomal recessive disorder, is characterised by recurrent attacks of fever and serositis, lasting 24-72 hours. Since 1972 colchicine has become the drug of choice for prophylaxis against FMF attacks and amyloidosis FMF-associated. Colchicine, an alkaloid neutral, is absorbed in the jejunum and ileum. It metabolised by liver and only small amounts are recovered unchanged in the urine. Really plasma half-life is prolonged in patients with liver or renal failure. Colchicine is able to prevent activation of neutrophils, binding beta-tubulin and making beta-tubulin-colchicine complexes; this way inhibits assembly of microtubules and mitotic spindle formation; moreover its mode of action includes modulation of chemokines, prostanoids production, inhibition of neutrophil and endothelial cell adhesion molecules. The minimal daily dose in adults is 1.0 mg/die, but in children there is not a definite dose. Since in vitro high dosages of colchicine stop mitosis, this drug might interfere with male and female fertility and with children growth, but, according to current guidelines and because of rare side effects of the drug, FMF patients are recommended to take colchicine. Since colchicine treatment is often complicated by frequent gastrointestinal side effects, by our experience, in order to improve colchicine tolerance we recommend: lactose-free diet and treatment of intestinal bacterial overgrowth and/or Hp-infection, assessed by breath tests. Since our data showed that 10-15% of FMF patients seem are non-responders or intolerant to colchicine, today we are working in the design of colchicine analogues which may have lesser toxicities and a larger therapeutic window.

Do the pleiotropic effects of statins in the vasculature predict a role in inflammatory diseases?

Pleiotropic effects are now described for the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (or statins) that might have utility in the context of chronic inflammatory autoimmune disease. Here we discuss the pharmacology and established uses of statins and in this context describe potential anti-inflammatory and immune-modulatory effects. An extensive in vitro data set defines roles for statins in modifying endothelial function, particularly with respect to adhesion molecule expression and apoptosis. Broader effects on leukocyte function have now emerged including altered adhesion molecule expression, cytokine and chemokine release and modulation of development of adaptive immune responses via altered MHC class II upregulation. In vivo data in several inflammatory models, including collagen-induced inflammatory arthritis and experimental autoimmune encephalomyelitis, suggest that such effects might have immune-modulatory potential. Finally, a recent clinical trial has demonstrated immunomodulatory effects for statins in patients with rheumatoid arthritis. Together with their known vasculoprotective effects, this growing body of evidence provides compelling support for longer-term trials of statin therapy in human disease such as rheumatoid arthritis.

Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules.

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1

Pathogenic effects of human herpesvirus 6 in human lymphoid tissue ex vivo.

Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that has been suggested to act as a cofactor in the progression of human immunodeficiency virus disease. However, the lack of suitable experimental models has hampered the elucidation of the mechanisms of HHV-6-mediated immune suppression. Here, we used ex vivo lymphoid tissue to investigate the cellular tropism and pathogenic mechanisms of HHV-6. Viral strains belonging to both HHV-6 subgroups (A and B) were able to productively infect human tonsil tissue fragments in the absence of exogenous stimulation. The majority of viral antigen-expressing cells were CD4(+) T lymphocytes expressing a nonnaive phenotype, while CD8(+) T cells were efficiently infected only with HHV-6A. Accordingly, HHV-6A infection resulted in the depletion of both CD4(+) and CD8(+) T cells, whereas in HHV-6B-infected tissue CD4(+) T cells were predominantly depleted. The expression of different cellular antigens was dramatically altered in HHV-6-infected tissues: whereas CD4 was upregulated, both CD46, which serves as a cellular receptor for HHV-6, and CD3 were downmodulated. However, CD3 downmodulation was restricted to infected cells, while the loss of CD46 expression was generalized. Moreover, HHV-6 infection markedly enhanced the production of the CC chemokine RANTES, whereas other cytokines and chemokines were only marginally affected. These results provide the first evidence, in a physiologically relevant study model, that HHV-6 can severely affect the physiology of secondary lymphoid organs through direct infection of T lymphocytes and modulation of key membrane receptors and chemokines.

Cytokine, chemokine, and costimulatory molecule modulation to enhance efficacy of HIV vaccines.

Understanding key intervention points in developing immune responses may allow the rational inclusion of biological adjuvants into vaccines that could potentiate the immune response both quantitatively and qualitatively and enhance effective memory responses. Cytokine and chemokine combinations can potentially help target antigen to the appropriate antigen presenting cell and initiate maturation of these presenting cells, attract cells expressing different chemokine receptors, steer cellular immune responses toward Th1 and CD8 CTL, and enhance systemic and mucosal IgG and secretory IgA antibodies and determine their isotype balance. Animal protection studies suggest that synergistic combinations of cytokines and immunomodulating molecules may be required to protect from a viral challenge. For example, GM-CSF has been shown to be synergistic with IL-12 or CD40 ligand for induction of CTL and for antiviral protection, and the triple combination of GM-CSF, IL-12, and TNF alpha appears to induce the most effective protection in some mouse models. Chemokine-antigen fusions have also been shown to enhance immunogenicity of the antigen. Combinations of costimulatory molecules have been found to be synergistic when incorporated in a vaccine. Combined use of newer more potent vaccine constructs, containing codon optimized epitopes, relevant CpG motifs, cytokines, costimulatory molecules and chemokines, used in heterologous prime-boost strategies with viral vector vaccines or recombinant proteins, might afford the most potent vaccine approaches yet developed. In this review we will discuss the application and delivery of cytokines, costimulatory molecules, and chemokines toward improving current vaccine strategies.

Hydrogen peroxide induces murine macrophage chemokine gene transcription via extracellular signal-regulated kinase- and cyclic adenosine 5'-monophosphate (cAMP)-dependent pathways: involvement of NF-kappa B, activator protein 1, and cAMP response element binding protein.

Hydrogen peroxide (H(2)O(2)) has been shown to act as a second messenger that activates chemokine expression. In the present study, we investigated the mechanisms underlying this cellular regulation in the murine macrophage cell line B10R. We report that H(2)O(2) increases mRNA expression of various chemokines, macrophage-inflammatory protein (MIP)-1alpha/CC chemokine ligand (CCL)3, MIP-1beta/CCL4, MIP-2/CXC chemokine ligand 2, and monocyte chemoattractant protein-1/CCL2, by activating the extracellular signal-regulated kinase (ERK) pathway and the nuclear translocation of the transcription factors NF-kappaB, AP-1, and CREB. Blockage of the ERK pathway with specific inhibitors against mitogen-activated protein kinase kinase 1/2 and ERK1/ERK2 completely abolished both the H(2)O(2)-mediated chemokine up-regulation and the activation of all NF studied. Similarly, selective inhibition of cAMP and NF-kappaB strongly down-regulated the induction of all chemokine transcripts as well as CREB and NF-kappaB activation, respectively. Of interest, we detected a significant decrease of NF-kappaB, AP-1, and CREB DNA binding activities by reciprocal competition for these binding sites when either specific cold oligonucleotides (NF-kappaB, AP-1, and CREB) or Abs against various transcription factor subunits (p50, p65, c-Fos, Jun B, c-Jun, and CREB-1) were added. These findings indicate that cooperation between ERK- and cAMP-dependent pathways seems to be required to achieve the formation of an essential transcriptional factor complex for maximal H(2)O(2)-dependent chemokine modulation. Finally, experiments performed with actinomycin D suggest that H(2)O(2)-mediated MIP-1beta mRNA up-regulation results from transcriptional control, whereas that of MIP-1alpha, MIP-2, and monocyte chemoattractant protein-1 is due to both gene transcription activation and mRNA posttranscriptional stabilization.

Heparin sequencing.

Heparin is a highly sulfated glycosaminoglycan widely used as an anticoagulant. Modifications in its relatively uniform structure appear to be key to its recognition and modulation of serine proteases, growth factors, chemokines, and extracellular proteins, as has been most clearly demonstrated in the antithrombin binding site. We sequenced the major oligosaccharides released from mastocytoma heparin by partial nitrous acid using a highly sensitive technique tailored for sequencing of metabolically radiolabeled heparin. It utilizes partial nitrous acid cleavage to allow simultaneous sequencing of the internal components of the oligosaccharide under investigation by specific lysosomal exoenzymes. Sequencing revealed that although the majority of the heparin disaccharides are N-, 2-O-, and 6-O-sulfated, the less sulfated disaccharides (lacking 2-O- or 6-O-sulfates) seem to be spaced out along the chain. The technique may be particularly useful for characterizing heparin from novel sources, such as the glial progenitor cells and Ascidia, as well as for sequencing protein binding sites.

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as modulators of both innate and adaptive immunity.

The structurally related neuropeptides VIP and PACAP are released within the lymphoid organs following antigenic stimulation, and modulate the function of inflammatory cells through specific receptors. In activated macrophages, VIP and PACAP inhibit the production of pro-inflammatory agents (cytokines, chemokines, and nitric oxide), and stimulate the production of the anti-inflammatory cytokine IL-10. These events are mediated through the VIP/PACAP effects on de novo expression or nuclear translocation of several transcription factors, i.e., NFkappaB, CREB, c-Jun, JunB, and IRF-1. The in vivo administration of VIP/PACAP results in a similar pattern of cytokine and chemokine modulation, which presumably mediates the protective effect of VIP/PACAP in septic shock. In addition, VIP/PACAP reduce the expression of the co-stimulatory molecules B7.1/B7.2, and the subsequent stimulatory activity of macrophages for T-helper cells. In T-cells expressing specific VIP/PACAP receptors, VIP and PACAP inhibit the expression of FasL through effects on NFkappaB, NFAT, and Egr2/3. The reduction of FasL expression has several biological consequences: inhibition of antigen-induced cell death in CD4 T-cells, inhibition of the FasL-mediated cytotoxicity of CD8 and CD4 effectors against direct and bystander targets, and promotion of long-term memory Th2 cells, through a positive effect on the survival of Th2, but not Th1, effectors. The various biological effects of VIP and PACAP are discussed within the range of a general anti-inflammatory model.

Update on colchicine and its mechanism of action.

Colchicine is a unique anti-inflammatory drug with respect to its limited clinical usefulness and its mode of action. Colchicine is mainly indicated for the treatment and prophylaxis of gout and familial Mediterranean fever. Its mode of action includes modulation of chemokine and prostanoid production and inhibition of neutrophil and endothelial cell adhesion molecules by which it interferes with the initiation and amplification of the joint inflammation. This paper discusses its adverse effects and indications.

Chemokine and chemokine receptor dynamics during genital chlamydial infection.

Current design strategies for vaccines against certain microbial pathogens, including Chlamydia trachomatis, require the induction and targeting of specific immune effectors to the local sites of infection known as the mucosal effector sites. Chemokines and their receptors are important mediators of leukocyte trafficking and of the controlled recruitment of specific leukocyte clonotypes during host defense against infections and during inflammation. We analyzed the dynamics of chemokine and chemokine receptor expression in genital mucosae during genital chlamydial infection in a murine model to determine how these molecular entities influence the development of immunity and the clearance of infection. A time course study revealed an increase of up to threefold in the levels of expression of RANTES, monocyte chemotactic protein 1 (MCP-1), gamma-interferon-inducible protein 10 (IP-10), macrophage inflammatory protein 1alpha (MIP-1alpha), and intercellular adhesion molecule type 1 (ICAM-1) after genital infection with the C. trachomatis agent of mouse pneumonitis. Peak levels of expression of RANTES, MCP-1, and MIP-1alpha occurred by day 7 after primary infection, while those of IP-10 and ICAM-1 peaked by day 21. Expression levels of these molecules decreased by day 42 after primary infection, by which time all animals had resolved the infection, suggesting an infection-driven regulation of expression. A rapid upregulation of expression of these molecules was observed after secondary infection. The presence of cells bearing the chemokine receptors CCR5 and CXCR3, known to be preferentially expressed on Th1 and dendritic cells, was also synchronous with the kinetics of immune induction in the genital tract and clearance of infection. Results demonstrated that genital chlamydial infection is associated with a significant induction of chemokines and chemokine receptors that are involved in the recruitment of Th1 cells into the site of infection. Future studies will focus on how selective modulation of chemokines and their receptors can be used to optimize long-term immunity against CHLAMYDIA:

Stimulant-dependent modulation of cytokines and chemokines by airway epithelial cells: cross talk between pulmonary epithelial and peripheral blood mononuclear cells.

Staphylococcal exotoxins (SE) and lipopolysaccharide (LPS) stimulate cells of the immune system to produce proinflammatory cytokines and chemokines which mediate septic shock and acute lung inflammation. A coculture of human peripheral blood mononuclear cells (PBMC) and pulmonary A549 epithelial cells was used to investigate inflammatory responses triggered by staphylococcal enterotoxin B (SEB), toxic shock syndrome toxin 1, and LPS. The levels of interleukin 1beta (IL-1beta), IL-6, gamma interferon-inducible protein 10, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1alpha, and RANTES were enhanced by 3.8-, 4.2-, 3.1-, 8.9-, 2-, and 2.9-fold, respectively, in cocultures of SEB-stimulated cells compared to in SEB-stimulated PBMC. In LPS-stimulated cocultures, only MCP-1 and RANTES levels were increased. These data suggest that the modulation of specific cytokines and chemokines is dependent on the stimulus and that there is bidirectional interaction between PBMC and lung epithelial cells to influence the immune response to these different stimuli.

Modulation of Chemokine Production and Inflammatory Responses in Interferon-γ- and Tumor Necrosis Factor-R1-Deficient Mice during Trypanosoma cruzi Infection

Infection with Trypanosoma cruzi causes a strong inflammatory reaction at the inoculation site and, later, in the myocardium. The present study investigates the role of cytokines as modulators of T. cruzi-induced chemokine expression in vivo and in vitro. In macrophage cultures, although the stimulation with interferon (IFN)-gamma increases the expression of IP-10, it blocks KC expression. Tumor necrosis factor (TNF)-alpha, on the other hand, potentiates KC, IP-10, macrophage inflammatory protein-1alpha, and JE/monocyte chemotatic protein-1 expression. Interleukin-10 and transforming growth factor-beta inhibited almost all chemokines tested. The role of IFN-gamma and TNF-alpha in chemokine modulation during infection was investigated in T. cruzi-infected IFN-gamma-deficient (GKO) or TNF-R1/p55-deficient (p55-/-) mice. The expression of chemokines detected in the inoculation site correlated with the infiltrating cell type observed. Although GKO mice had a delayed and intense neutrophilic infiltrate correlating with the expression of KC and macrophage inflammatory protein-2, none of the above was observed in p55-/- mice. The detection of infiltrating T cells, Mig, and IP-10 in the myocardium was observed in wild-type and p55-/-, but not in GKO mice. Together, these results suggest that the regulatory roles of IFN-gamma and TNF-alpha on chemokine expression may play a crucial role in the modulation of the inflammatory response during T. cruzi infection and mediate resistance to infection.