IL-6 acts on endothelial cells to preferentially increase their adherence for lymphocytes

Watson, Campbell D.; Whittaker, Sean; Smith, N.P.; Vora, AJ; Dumonde, D. C.; Brown, Kenneth A.

doi:10.1046/j.1365-2249.1996.d01-717.x

Cited by 146 publications

(106 citation statements)

References 33 publications

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“…Our data provide the first demonstration, to our knowledge, of LPS and S1P cooperation to induce the expression of proinflammatory molecules such as the cytokine IL-6, a member of the acute-phase reactant family known to facilitate leukocyte adhesion to the vascular wall and to have an effect on other cells in the vascular wall, such as smooth muscle cells (32). Our results are in accordance with the cooperation of TLR4 and S1P receptors to enhance inflammatory cytokine production in human gingival epithelial cells (33).…”

Section: Discussionmentioning

confidence: 67%

Lipopolysaccharide and Sphingosine-1-Phosphate Cooperate To Induce Inflammatory Molecules and Leukocyte Adhesion in Endothelial Cells

Fernández‐Pisonero

Dueñas

Barreiro

et al. 2012

The Journal of Immunology

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Given that TLRs and sphingosine-1-phosphate (S1P) are key players in inflammation, we explored the potential interplay between TLRs and S1P in the adhesion/inflammatory pathways in primary human endothelial cells. As determined by Western blot and flow cytometry, cells treated with LPS (a TLR4 ligand) and S1P showed significantly enhanced expression of adhesion molecules such as ICAM-1 and E-selectin compared with the effect of either ligand alone. Cell-type differences on E-selectin upregulation were observed. In contrast, no cooperation effect on ICAM-1 or E-selectin was observed with a TLR2/TLR1 ligand. Consistent with an increase in adhesion molecule expression, endothelial cell treatment with LPS plus S1P significantly enhanced adhesion of PBMCs under shear stress conditions compared with the effect of either ligand alone and exhibited comparable levels of cell adhesion strength as those after TNF-α treatment. Moreover, LPS and S1P cooperated to increase the expression of proinflammatory molecules such as IL-6, cyclooxygenase-2, and prostacyclin, as determined by ELISA and Western blot. The analysis of signaling pathways revealed the synergistic phosphorylation of ERK upon LPS plus S1P treatment of HUVEC and human aortic endothelial cells and cell-type differences on p38 and NF-κB activation. Moreover, pharmacological and small interfering RNA experiments disclosed the involvement of S1P1/3 and NF-κB in the cooperation effect and that cell origin determines the S1P receptors and signaling routes involved. Sphingosine kinase activity induction upon LPS plus S1P treatment suggests S1P– Sphingosine kinase axis involvement. In summary, LPS and S1P cooperate to increase proinflammatory molecules in endothelial cells and, in turn, to augment leukocyte adhesion, thus exacerbating S1P-mediated proadhesive/proinflammatory properties.

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Section: Discussionmentioning

confidence: 67%

Lipopolysaccharide and Sphingosine-1-Phosphate Cooperate To Induce Inflammatory Molecules and Leukocyte Adhesion in Endothelial Cells

Fernández‐Pisonero

Dueñas

Barreiro

et al. 2012

The Journal of Immunology

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“…In contrast, activation of the immune system within the central nervous system (CNS) has been found to play a pivotal role in the pathogenesis of lupus psychosis, as evidenced by enhanced intrathecal immunoglobulin synthesis (11). Of note, monocytes have been shown to modulate the function of endothelial cells (12)(13)(14). Thus, TNF␣ released by coexisting monocytes promotes transendothelial migration of activated lymphocytes (12,13).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, TNF␣ released by coexisting monocytes promotes transendothelial migration of activated lymphocytes (12,13). In addition, IL-6 has been shown to increase adherence of endothelial cells for lymphocytes, facilitating the recruitment of lymphocytes into nonlymphoid tissues (14). It is therefore possible that anti-P antibodies might be involved in the recruitment of immunocompetent cells into the site of inflammation, including the CNS, by stimulating their transendothelial migration through upregulation of monocyte production of TNF␣ and IL-6.…”

Section: Discussionmentioning

confidence: 99%

Anti–ribosomal P protein antibody in human systemic lupus erythematosus up‐regulates the expression of proinflammatory cytokines by human peripheral blood monocytes

Nagai¹,

Arinuma²,

Yanagida³

et al. 2005

Arthritis & Rheumatism

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Objective. Autoantibodies to ribosomal P proteins (anti-P antibodies) are detected in 12-16% of patients with systemic lupus erythematosus (SLE) and have been found to be associated with some manifestations of the disease, including lupus psychosis and hepatitis. Recent studies have disclosed that anti-P antibodies react with activated T cells but not with B cells, suggesting possible direct effects of anti-P antibodies on immune regulation. The present study was designed to explore the presence of the epitope recognized by anti-P antibodies on human peripheral blood monocytes.Methods. Highly purified peripheral blood monocytes obtained from healthy donors were cultured with or without interferon-␥ (IFN␥) in the presence of either anti-P antibodies purified by affinity chromatography from the sera of patients with SLE or control IgG.Results. Flow cytometry analysis disclosed that fresh (day 0) monocytes did not express the ribosomal P epitope, whereas expression of the ribosomal P epitope was induced on annexin V-negative monocytes after activation through plastic adherence for 48 hours. More important, anti-P antibodies (compared with normal IgG or IgG from SLE patients devoid of anti-P antibodies) enhanced the production of tumor necrosis factor ␣ (TNF␣) and interleukin-6 (IL-6) by activated monocytes. Accordingly, anti-P antibodies also up-regulated the expression of TNF␣ and IL-6 messenger RNA in activated monocytes. Of note, F(ab ) 2 fragments of anti-P antibodies, which do not result in Fc␥ receptor (Fc␥R) crosslinking, also effectively up-regulated the expression of TNF␣ and IL-6.Conclusion. These results indicate that human peripheral blood monocytes express the ribosomal P epitope upon activation, irrespective of induction of apoptosis. Moreover, the data suggest that anti-P antibodies might modify a variety of inflammatory responses through up-regulation of the expression of proinflammatory cytokines in monocytes, in a manner that does not involve Fc␥R crosslinking.Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by the expression of a variety of autoantibodies. Autoantibodies to ribosomal P proteins (anti-P antibodies) are detected in 12-16% of patients with SLE (1). Anti-P antibodies are directed to 3 phosphoproteins (P0, P1, and P2), which are located on the larger 60S subunit of eukaryotic ribosomes and have molecular weights of 38 kd, 19 kd, and 17 kd, respectively (1). Ribosomal P proteins share a common linear determinant that is present in the carboxyl-terminal 22-amino acid sequence (1). Previous and recent studies have disclosed the association of anti-P antibodies with neuropsychiatric disease in SLE (2,3). Moreover, it was recently shown that antiribosomal P is strongly associated with hepatitis and

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“…We have found that LT or LT mutants significantly enhanced recruitment of cells to LN draining the site of inoculation (E. J. Ryan, E. McNeela, and K. H. G. Mills, unpublished observations). Enhancement of cellular infiltration may be mediated in part by the ability of the toxins to induce the production of IL-6, which has chemotactic properties for lymphocytes (34), and the C-X-C chemokine, MIP-2, the putative functional homologue of human IL-8. LT, LTR72, and LTK63 differentially effected the expression of certain costimulatory molecules on the cells of the innate immune system.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Innate and Acquired Immune Responses by Escherichia coli Heat-Labile Toxin: Distinct Pro- and Anti-Inflammatory Effects of the Nontoxic AB Complex and the Enzyme Activity

Ryan

McNeela

Pizza

et al. 2000

The Journal of Immunology

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We have examined the roles of enzyme activity and the nontoxic AB complex of heat-labile toxin (LT) from Escherichia coli on its adjuvant and immunomodulatory properties. LTK63, an LT mutant that is completely devoid of enzyme activity, enhanced Th1 responses to coinjected Ags at low adjuvant dose. In contrast, LTR72, a partially detoxified mutant, enhanced Th2 responses and when administered intranasally to mice before infection with Bordetella pertussis suppressed Th1 responses and delayed bacterial clearance from the lungs. LTR72 or wild-type LT inhibited Ag-induced IFN-γ production by Th1 cells, and LT enhanced IL-5 production by Th2 cells in vitro. Each of the toxins enhanced B7-1 expression on macrophages, but enhancement of B7-2 expression was dependent on enzyme activity. We also observed distinct effects of the nontoxic AB complex and enzyme activity on inflammatory cytokine production. LT and LTR72 suppressed LPS and IFN-γ induced TNF-α and IL-12 production, but enhanced IL-10 secretion by macrophages in vitro and suppressed IL-12 production in vivo in a murine model of LPS-induced shock. In contrast, LTK63 augmented the production of IL-12 and TNF-α. Furthermore, LTK63 enhanced NF-κB translocation, whereas low doses of LTR72 or LT failed to activate NF-κB, but stimulated cAMP production. Thus, E. coli LT appears to be capable of suppressing Th1 responses and enhancing Th2 responses through the modulatory effects of enzyme activity on NF-κB activation and IL-12 production. In contrast, the nontoxic AB complex can stimulate acquired immune responses by activating components of the innate immune system.

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IL-6 acts on endothelial cells to preferentially increase their adherence for lymphocytes

Cited by 146 publications

References 33 publications

Lipopolysaccharide and Sphingosine-1-Phosphate Cooperate To Induce Inflammatory Molecules and Leukocyte Adhesion in Endothelial Cells

Lipopolysaccharide and Sphingosine-1-Phosphate Cooperate To Induce Inflammatory Molecules and Leukocyte Adhesion in Endothelial Cells

Anti–ribosomal P protein antibody in human systemic lupus erythematosus up‐regulates the expression of proinflammatory cytokines by human peripheral blood monocytes

Modulation of Innate and Acquired Immune Responses by Escherichia coli Heat-Labile Toxin: Distinct Pro- and Anti-Inflammatory Effects of the Nontoxic AB Complex and the Enzyme Activity

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