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Proinflammatory Activity (proinflammatory + activity)

Distribution by Scientific Domains
Medical Sciences75%

Selected Abstracts

The proinflammatory activity of recombinant serum amyloid A is not shared by the endogenous protein in the circulation

ARTHRITIS & RHEUMATISM, Issue 6 2010
Lena Björkman
Objective Elevated serum levels of the acute-phase protein serum amyloid A (SAA) are a marker for active rheumatoid arthritis (RA), and SAA can also be found in the tissues of patients with active RA. Based on a number of studies with recombinant SAA (rSAA), the protein has been suggested to be a potent proinflammatory mediator that activates human neutrophils, but whether endogenous SAA shares these proinflammatory activities has not been directly addressed. The present study was undertaken to investigate whether SAA in the plasma of patients with RA possesses proinflammatory properties and activates neutrophils in a manner similar to that of the recombinant protein. Methods Neutrophil activation was monitored by flow cytometry, based on L-selectin shedding from cell surfaces. Whole blood samples from healthy subjects and from RA patients with highly elevated SAA levels were studied before and after stimulation with rSAA as well as purified endogenous SAA. Results Recombinant SAA potently induced cleavage of L-selectin from neutrophils and in whole blood samples. Despite highly elevated SAA levels, L-selectin was not down-regulated on RA patient neutrophils as compared with neutrophils from healthy controls. Spiking SAA-rich whole blood samples from RA patients with rSAA, however, resulted in L-selectin shedding. In addition, SAA purified from human plasma was completely devoid of neutrophil- or macrophage-activating capacity. Conclusion The present findings show that rSAA is proinflammatory but that this activity is not shared by endogenous SAA, either when present in the circulation of RA patients or when purified from plasma during an acute-phase response. [source]

The interferon-inducible gene IFI16 secretome of endothelial cells drives the early steps of the inflammatory response

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2010
Rossella Baggetta
Abstract The IFN-inducible human IFI16 gene is highly expressed in endothelial cells as well as epithelial and hematopoietic tissues. Previous gene array analysis of human umbilical vein endothelial cells overexpressing IFI16 has revealed an increased expression of genes involved in inflammation and apoptosis. In this study, protein array analysis of the IFI16 secretome showed an increased production of chemokines, cytokines and adhesion molecules responsible for leukocyte chemotaxis. Functional analysis of the promoter for CCL20, the chemokine responsible for leukocyte recruitment in the early steps of inflammation, by site-specific mutation demonstrated that NF-,B is the main mediator of CCL20 induction at the transcriptional level. Finally, both Langerhans DC and B-lymphocyte migration triggered by supernatants from IFI16-overexpressing endothelial cells was partially inhibited by Ab inactivating CCL4, CCL5 and CCL20 chemokines. Altogether, these results demonstrate that the IFI16 gene, through its secretome, regulates proinflammatory activity of endothelial cells, thus corroborating its role in the early steps of inflammation. [source]

Modulation of Monocyte-Macrophage Function with ,-Tocopherol: Implications for Atherosclerosis

NUTRITION REVIEWS, Issue 1 2002
Sridevi Devaraj PhD
Cardiovascular disease is the leading cause of morbidity and mortality in the Western world. Monocyte-macrophages are crucial cells in atherogenesis. Several lines of evidence suggest that antioxidants, especially , -tocopherol, have beneficial effects with regard to cardiovascular disease. , -Tocopherol has beneficial effects on cell functions that are pivotal in atherogenesis. , -Tocopherol inhibits platelet aggregation and proinflammatory activity of monocytes. In vitro data also support an effect of , -tocopherol on smooth muscle cell proliferation and endothelial function. Finally, recent data support an effect of , -tocopherol on macrophage function. The mounting evidence from in vitro and in vivo studies provides a sound scientific basis for , -tocopherol supplementation. Further clinical trials are required, however, before a definitive recommendation can be made for primary and secondary prevention of heart disease. [source]

Proinflammatory role of the Th17 cytokine interleukin-22 in collagen-induced arthritis in C57BL/6 mice

ARTHRITIS & RHEUMATISM, Issue 2 2009
Lies Geboes
Objective To investigate the role of interleukin-22 (IL-22) in collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. Methods C57BL/6 mice were immunized with type II collagen (CII) in Freund's incomplete adjuvant with added Mycobacterium tuberculosis, and levels of IL-22 and its specific receptor, IL-22 receptor type I (IL-22RI), were measured in sera and tissue by enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction analysis. Clinical and histologic signs of arthritis were recorded and compared with those in C57BL/6 mice deficient in the IL-22 gene (IL-22,/,). Humoral and cellular immune responses against CII were analyzed. In vitro osteoclastogenesis assays were performed on splenocytes. Results Upon immunization with CII in Freund's incomplete adjuvant plus heat-killed Mycobacterium tuberculosis, sera from C57BL/6 mice were found to contain high levels of IL-22, and the specific IL-22RI was expressed in lymphoid tissue, including splenocytes. IL-22,/, mice were less susceptible to CIA than were wild-type mice, as evidenced by their decreased incidence of arthritis and decreased pannus formation. Remarkably, the less severe form of arthritis in IL-22,/, mice was associated with increased production of CII-specific and total IgG antibodies, whereas cellular CII responses were unchanged. In vitro, IL-22 was found to promote osteoclastogenesis, a process that might contribute to its proinflammatory activity in CIA. Conclusion Endogenous IL-22 plays a proinflammatory role in CIA in C57BL/6 mice. Our data also indicate that IL-22 promotes osteoclastogenesis and regulates antibody production. [source]

Selective elimination of synovial inflammatory macrophages in rheumatoid arthritis by an Fc, receptor I,directed immunotoxin

ARTHRITIS & RHEUMATISM, Issue 5 2003
Joel A. G. Van Roon
Objective To determine whether monocyte/macrophages from rheumatoid arthritis (RA) patients can be selectively eliminated by a toxin-conjugated antibody CD64,ricin A (CD64-RiA) directed toward the high-affinity receptor for IgG (Fc,RI), exploiting the capacity of Fc,RI to efficiently endocytose antibody which it has bound. Methods Mononuclear cells from peripheral blood (PB) and synovial fluid (SF) obtained from RA patients were cultured in the presence of CD64-RiA. Cell death of monocyte/macrophages was measured by phenotypic changes (light-scatter patterns and CD14 and Fc,RI expression) and apoptosis (nuclear DNA fragmentation). We then tested whether CD64-RiA,induced cell death of macrophages affected their capacity to stimulate antigen-induced lymphocyte proliferation and to secrete cytokines. Additionally, the capacity of CD64-RiA to inhibit proinflammatory activity and cartilage degradation by RA synovial tissue explants was evaluated. Results Inflammatory macrophages from RA SF expressed elevated levels of Fc,RI and were selectively eliminated by CD64-RiA via apoptotic cell death. Monocyte/macrophages from RA PB, which had lower levels of Fc,RI expression, were much less affected. Induction of SF macrophage apoptosis was associated with efficient inhibition of antigen-induced lymphocyte proliferation and a reduction in tumor necrosis factor , (TNF,) release. Consistent with these effects on SF macrophages, CD64-RiA also inhibited TNF, production, interleukin-1, production, and cartilage-degrading activity of RA synovial tissue explants. Conclusion Together, these data underscore the crucial role of synovial macrophages in RA joint inflammation and indicate that selective elimination of these cells through Fc,RI-directed immunotoxins could be a novel approach to the treatment of RA. [source]

Eicosanoid-mediated proinflammatory activity of Pseudomonas aeruginosa ExoU

CELLULAR MICROBIOLOGY, Issue 12 2005
A. M. Saliba
Summary As Pseudomonas aeruginosa ExoU possesses two functional blocks of homology to calcium-independent (iPLA2) and cytosolic phospholipase A2 (cPLA2), we addressed the question whether it would exhibit a proinflammatory activity by enhancing the synthesis of eicosanoids by host organisms. Endothelial cells from the HMEC-1 line infected with the ExoU-producing PA103 strain exhibited a potent release of arachidonic acid (AA) that could be significantly inhibited by methyl arachidonyl fluorophosphonate (MAFP), a specific PLA2 inhibitor, as well as significant amounts of the cyclooxygenase (COX)-derived prostaglandins PGE2 and PGI2. Cells infected with an isogenic mutant defective in ExoU synthesis did not differ from non-infected cells in the AA release and produced prostanoids in significantly lower concentrations. Infection by PA103 induced a marked inflammatory response in two different in vivo experimental models. Inoculation of the parental bacteria into mice footpads led to an early increase in the infected limb volume that could be significantly reduced by inhibitors of both COX and lipoxygenase (ibuprofen and NDGA respectively). In an experimental respiratory infection model, bronchoalveolar lavage (BAL) from mice instilled with 104 cfu of PA103 exhibited a marked influx of inflammatory cells and PGE2 release that could be significantly reduced by indomethacin, a non-selective COX inhibitor. Our results suggest that ExoU may contribute to P. aeruginosa pathogenesis by inducing an eicosanoid,mediated inflammatory response of host organisms. [source]

Cellular autoreactivity against heat shock protein 60 in renal transplant patients: peripheral and graft-infiltrating responses

CLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 1 2006
C. Caldas
Summary Autoreactivity to heat shock protein 60 (Hsp60) has been implicated in the pathogenesis and regulation of chronic inflammation, especially in autoimmune diseases. In transplantation, there is a lack of information regarding the cytokine profile and specificity of cells that recognize self-Hsp60 as well as the kinetics of autoreactivity following transplantation. We studied the cellular reactivity of peripheral and graft-infiltrating lymphocytes against Hsp60 in renal transplant patients. Cytokine production induced by this protein in peripheral blood mononuclear cells indicated a predominance of interleukin (IL)-10 during the late post-transplantation period, mainly in response to intermediate and C-terminal peptides. Patients with chronic rejection presented reactivity to Hsp60 with a higher IL-10/interferon (IFN)-, ratio compared to long-term clinically stable patients. Graft-infiltrating T cell lines, cocultured with antigen-presenting cells, preferentially produced IL-10 after Hsp60 stimulation. These results suggest that, besides its proinflammatory activity, autoreactivity to Hsp60 in transplantation may also have a regulatory role. [source]