scholarly journals Defective inflammatory response in interleukin 6-deficient mice.

1994 ◽  
Vol 180 (4) ◽  
pp. 1243-1250 ◽  
Author(s):  
E Fattori ◽  
M Cappelletti ◽  
P Costa ◽  
C Sellitto ◽  
L Cantoni ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Interleukin 6 ◽  
Tissue Damage ◽  
Acute Phase Proteins ◽  
Host Responses ◽  
Tnf Alpha ◽  
Wild Type ◽  
Compensatory Mechanisms ◽  
Necrosis Factor Alpha ◽  
Deficient Mice

Systemic and localized inflammation elicit a number of host responses which include fever, cachexia, hypoglycemia, and major changes in the concentration of liver plasma proteins. Interleukin 6 (IL-6) is considered an important mediator of the inflammatory response, together with IL-1 and tumor necrosis factor alpha (TNF-alpha). The purpose of this study was to unequivocally determine the role of IL-6 in these phenomena making use of IL-6-deficient mice that we have recently generated by gene targeting. We report here that in the absence of IL-6, mice are unable to mount a normal inflammatory response to localized tissue damage generated by turpentine injection. The induction of acute phase proteins is dramatically reduced, mice do not lose body weight and only suffer from mild anorexia and hypoglycemia. In contrast, when systemic inflammation is elicited through the injection of bacterial lipopolysaccharide (LPS), these parameters are altered to the same extent both in wild-type and IL-6-deficient mice, demonstrating that under these conditions IL-6 function is dispensable. Moreover, we show that LPS-treated IL-6-deficient mice produce three times more TNF-alpha than wild-type controls, suggesting that increased TNF-alpha production might be one of the compensatory mechanisms through which a normal response to LPS is achieved in the absence of IL-6. We also show that corticosterone is normally induced in IL-6-deficient mice, demonstrating that IL-6 is not required for the activation of the hypothalamic-pituitary-adrenal axis. Our results reinforce the idea that different patterns of cytokines are involved in systemic and localized tissue damage, and identify IL-6 as an essential mediator of the inflammatory response to localized inflammation.

scholarly journals Phenotypic Switching in Cryptococcus neoformans Contributes to Virulence by Changing the Immunological Host Response

2008 ◽  
Vol 76 (9) ◽  
pp. 4322-4331 ◽  
Author(s):  
Abraham Guerrero ◽  
Bettina C. Fries
Keyword(s):  
Inflammatory Response ◽  
Cryptococcus Neoformans ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Interleukin 10 ◽  
Host Responses ◽  
Phenotypic Switching ◽  
Wild Type ◽  
Necrosis Factor Alpha

ABSTRACT Cryptococcus neoformans is an encapsulated opportunistic organism that can undergo phenotypic switching. In this process, the parent smooth colony (SM) switches to a more virulent mucoid colony (MC) variant. The host responses mounted against the SM and MC variants differ, and lower tissue interleukin 10 (IL-10) levels are consistently observed in lungs of MC-infected C57BL/6 and BALB/c mice. This suggested different roles of this cytokine in SM and MC infections. The objective of this study was to compare survival rates and characterize the host responses of SM- and MC-infected IL-10-depleted (IL-10−/−) mice, which exhibit a Th1-polarized immune response and are considered resistant hosts. As expected, SM-infected IL-10−/− mice survived longer than wild-type mice, whereas MC-infected IL-10−/− mice did not exhibit a survival benefit. Consistent with this observation, we demonstrated marked differences in the inflammatory responses of SM- and MC-infected IL-10−/− and wild-type mice. This included a more Th1-polarized inflammatory response with enhanced recruitment of macrophages and natural killer and CD8 cells in MC- than in SM-infected IL-10−/− and wild-type mice. In contrast, both SM-infected IL-10−/− and wild-type mice exhibited higher recruitment of CD4 cells, consistent with enhanced survival and differences in recruitment and Th1/Th2 polarization. Lung tissue levels of IL-21, IL-6, IL-4, transforming growth factor beta, IL-12, and gamma interferon were higher in MC-infected IL-10−/− and wild-type mice than in SM-infected mice, whereas tumor necrosis factor alpha levels were higher in SM-infected IL-10−/− mice. In conclusion, the MC variant elicits an excessive inflammatory response in a Th1-polarized host environment, and therefore, the outcome is negatively affected by the absence of IL-10.

TNF-alpha induces selectin-mediated leukocyte rolling in mouse cremaster muscle arterioles

1997 ◽  
Vol 272 (3) ◽  
pp. H1391-H1400 ◽  
Author(s):  
E. J. Kunkel ◽  
U. Jung ◽  
K. Ley
Keyword(s):  
Tnf Alpha ◽  
Leukocyte Rolling ◽  
Cremaster Muscle ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Rolling Velocity ◽  
Shear Rates ◽  
Factor Alpha ◽  
Wall Shear ◽  
Deficient Mice

Leukocyte rolling is commonly restricted to venules and mediated by selectins expressed both on leukocytes (L-selectin) and the vascular endothelium (P- and E-selectin). We show here that 2- to 3-h tumor necrosis factor-alpha (TNF-alpha) stimulation of the mouse cremaster muscle induces rolling in arterioles (diameters 30-70 microm; wall shear rates 225-1,770 s(-1)). Weak P-selectin expression was detected on arteriolar endothelium of TNF-alpha-stimulated cremaster muscles. No rolling was observed in arterioles smaller than 30 microm (wall shear rates 1,500-3,250 s(-1)). The arteriolar rolling flux fraction in wild-type mice averaged approximately 5% and rolling was blocked by the P-selectin monoclonal antibody (MAb) RB40.34. Rolling in L- and E-selectin-deficient mice was similar to that in wild-type mice and was also blocked by the MAb RB40.34. Rolling was completely absent in arterioles of P-selectin-deficient mice. The average rolling velocity in arterioles of wild-type and L-selectin-deficient mice was approximately 50 microm/s but increased to approximately 110 microm/s in E-selectin-deficient mice and after injection of the blocking E-selectin MAb 9A9 in wild-type mice. We conclude that TNF-alpha treatment induces P-selectin-dependent rolling in arterioles that requires E-selectin for rolling at normal velocities.

scholarly journals IkappaBalpha deficiency results in a sustained NF-kappaB response and severe widespread dermatitis in mice.

1996 ◽  
Vol 16 (5) ◽  
pp. 2341-2349 ◽  
Author(s):  
J F Klement ◽  
N R Rice ◽  
B D Car ◽  
S J Abbondanzo ◽  
G D Powers ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Nuclear Localization ◽  
Nuclear Translocation ◽  
Tnf Alpha ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Cultured Fibroblasts ◽  
Nf Kappab ◽  
Nuclear Levels ◽  
Deficient Mice

The ubiquitous transcription factor NF-kappaB is an essential component in signal transduction pathways, in inflammation, and in the immune response. NF-kappaB is maintained in an inactive state in the cytoplasm by protein-protein interaction with IkappaBalpha. Upon stimulation, rapid degradation of IkappaBalpha allows nuclear translocation of NF-kappaB. To study the importance of IkappaBalpha in signal transduction, IkappaBalpha-deficient mice were derived by gene targeting. Cultured fibroblasts derived from IkappaBalpha-deficient embryos exhibit levels of NF-kappaB1, NF-kappaB2, RelA, c-Rel, and IkappaBbeta similar to those of wild-type fibroblasts. A failure to increase nuclear levels of NF-kappaB indicates that cytoplasmic retention of NF-kappaB may be compensated for by other IkappaB proteins. Treatment of wild-type cells with tumor necrosis factor alpha (TNF-alpha) resulted in rapid, transient nuclear localization of NF-kappaB. IkappaBalpha-deficient fibroblasts are also TNF-alpha responsive, but nuclear localization of NF-kappaB is prolonged, thus demonstrating that a major irreplaceable function Of IkappaBalpha is termination of the NF-kappaB response. Consistent with these observations, and with IkappaBalpha and NF-kappaB's role in regulating inflammatory and immune responses, is the normal development Of IkappaBalpha-deficient mice. However, growth ceases 3 days after birth and death usually occurs at 7 to 10 days of age. An increased percentage of monocytes/macrophages was detected in spleen cells taken from 5-, 7-, and 9-day-old pups. Death is accompanied by severe widespread dermatitis and increased levels of TNF-alpha mRNA in the skin.

scholarly journals CLEC5A-Mediated Enhancement of the Inflammatory Response in Myeloid Cells Contributes to Influenza Virus Pathogenicity In Vivo

2016 ◽  
Vol 91 (1) ◽  
Author(s):  
Ooiean Teng ◽  
Szu-Ting Chen ◽  
Tsui-Ling Hsu ◽  
Sin Fun Sia ◽  
Suzanne Cole ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Proinflammatory Cytokines ◽  
Inflammatory Responses ◽  
Myeloid Cells ◽  
Influenza Viruses ◽  
Host Responses ◽  
Wild Type ◽  
Survival Difference ◽  
Deficient Mice

ABSTRACT Human infections with influenza viruses exhibit mild to severe clinical outcomes as a result of complex virus-host interactions. Induction of inflammatory mediators via pattern recognition receptors may dictate subsequent host responses for pathogen clearance and tissue damage. We identified that human C-type lectin domain family 5 member A (CLEC5A) interacts with the hemagglutinin protein of influenza viruses expressed on lentiviral pseudoparticles through lectin screening. Silencing CLEC5A gene expression, blocking influenza-CLEC5A interactions with anti-CLEC5A antibodies, or dampening CLEC5A-mediated signaling using a spleen tyrosine kinase inhibitor consistently reduced the levels of proinflammatory cytokines produced by human macrophages without affecting the replication of influenza A viruses of different subtypes. Infection of bone marrow-derived macrophages from CLEC5A-deficient mice showed reduced levels of tumor necrosis factor alpha (TNF-α) and IP-10 but elevated alpha interferon (IFN-α) compared to those of wild-type mice. The heightened type I IFN response in the macrophages of CLEC5A-deficient mice was associated with upregulated TLR3 mRNA after treatment with double-stranded RNA. Upon lethal challenges with a recombinant H5N1 virus, CLEC5A-deficient mice showed reduced levels of proinflammatory cytokines, decreased immune cell infiltration in the lungs, and improved survival compared to the wild-type mice, despite comparable viral loads noted throughout the course of infection. The survival difference was more prominent at a lower dose of inoculum. Our results suggest that CLEC5A-mediated enhancement of the inflammatory response in myeloid cells contributes to influenza pathogenicity in vivo and may be considered a therapeutic target in combination with effective antivirals. Well-orchestrated host responses together with effective viral clearance are critical for optimal clinical outcome after influenza infections. IMPORTANCE Multiple pattern recognition receptors work in synergy to sense viral RNA or proteins synthesized during influenza replication and mediate host responses for viral control. Well-orchestrated host responses may help to maintain the inflammatory response to minimize tissue damage while inducing an effective adaptive immune response for viral clearance. We identified that CLEC5A, a C-type lectin receptor which has previously been reported to mediate flavivirus-induced inflammatory responses, enhanced induction of proinflammatory cytokines and chemokines in myeloid cells after influenza infections. CLEC5A-deficient mice infected with influenza virus showed reduced inflammation in the lungs and improved survival compared to that of the wild-type mice despite comparable viral loads. The survival difference was more prominent at a lower dose of inoculum. Collectively, our results suggest that dampening CLEC5A-mediated inflammatory responses in myeloid cells reduces immunopathogenesis after influenza infections.

Involvement of a NF-kappa B-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines

1990 ◽  
Vol 10 (2) ◽  
pp. 561-568
Author(s):  
H Shimizu ◽  
K Mitomo ◽  
T Watanabe ◽  
S Okamoto ◽  
K Yamamoto
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcriptional Activation ◽  
Interleukin 6 ◽  
Interleukin 1 ◽  
Tnf Alpha ◽  
Nuclear Factor ◽  
Nf Kappa B ◽  
Necrosis Factor Alpha ◽  
Mediators Of Inflammation

Interleukin-6 (IL-6) is one of the major mediators of inflammation, and its expression is inducible by the other inflammatory lymphokines, interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). We demonstrate that a common IL-6 promoter element, termed inflammatory lymphokine-responsive element (ILRE), is important for induction of IL-6 gene expression by IL-1 and TNF-alpha despite possible differences in the mechanisms of action of these lymphokines. Remarkably, the ILRE sequence, located between -73 to -63 relative to the mRNA cap site, is highly homologous to NF-kappa B transcription factor-binding motifs and binds an IL-1-TNF-alpha-inducible nuclear factor; the sequence specificities, binding characteristics, and subcellular localizations of this factor are indistinguishable from those of NF-kappa B. In addition, mutations of the ILRE sequence which impair the binding of this nuclear factor abolished the induction of IL-6 gene expression by IL-1 and TNF-alpha in vivo. These results indicate that a nuclear factor indistinguishable from NF-kappa B is involved in the transcriptional activation of the IL-6 gene by IL-1 and TNF-alpha.

scholarly journals Inducible production of interleukin-6 by human polymorphonuclear neutrophils: role of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha

Blood ◽  
1990 ◽  
Vol 75 (10) ◽  
pp. 2049-2052 ◽  
Author(s):  
NA Cicco ◽  
A Lindemann ◽  
J Content ◽  
P Vandenbussche ◽  
M Lubbert ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Polymorphonuclear Neutrophils ◽  
Tnf Alpha ◽  
Necrosis Factor Alpha ◽  
Gm Csf ◽  
Factor Alpha ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Necrosis Factor

Abstract The recent demonstration of the ability of human polymorphonuclear neutrophils (PMN) to secrete various cytokines in response to the granulocyte activator granulocyte-macrophage colony-stimulating factor (GM-CSF) but not to other cytokines, has led to the identification of PMN as biosynthetically active cells. In this study we have investigated the ability of PMN to secrete interleukin-6 (IL-6), a molecule known to be involved in inflammatory reactions. Using RNA blotting analysis and bioassays, we show that PMN could be induced to synthesize transcripts specific for IL-6, indistinguishable in size from IL-6 mRNA produced by activated human macrophages. Consequently, PMN released IL-6-like activity into their culture supernatants that could be neutralized by monospecific anti-IL-6 antibody. Interleukin-6 secretion by PMN, however, required previous stimulation with GM-CSF or tumor necrosis factor-alpha (TNF-alpha), whereas other cytokines, including interleukin-3 (IL-3), granulocyte-CSF (G-CSF), macrophage-CSF (M-CSF), interferon gamma (IFN-gamma), and lymphotoxin (LT), failed to induce IL-6 mRNA accumulation and protein secretion by PMN. Similar to GM-CSF and TNF-alpha, other compounds, including the inhibitor of protein synthesis cyclohexemide (CHX), endotoxin (Escherichia coli- derived lipopolysaccharide), and phorbol myristate acetate (PMA) (but not the chemoattractant N-formyl-methionyl-leucyl-phenylalanine [FMLP]), induced detectable levels of IL-6 transcripts in PMN.

scholarly journals Effect of Exercise Training on Interleukin-6, Tumour Necrosis Factor Alpha and Functional Capacity in Heart Failure

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Neil A. Smart ◽  
Alf I. Larsen ◽  
John P. Le Maitre ◽  
Almir S. Ferraz
Keyword(s):  
Exercise Training ◽  
Tumour Necrosis Factor ◽  
Interleukin 6 ◽  
Tumour Necrosis ◽  
Tumour Necrosis Factor Alpha ◽  
Tnf Alpha ◽  
Necrosis Factor Alpha ◽  
Cytokine Levels ◽  
Factor Alpha ◽  
Necrosis Factor

Background. We pooled data from four studies, to establish whether exercise training programs were able to modulate systemic cytokine levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). A second aim was to establish if differences in ExT regimens are related to degree of change in cytokines and peak VO2.Methods. Data from four centres relating to training protocol, exercise capacity, and cytokine measures (TNF-alpha and IL-6) were pooled for analysis.Results. Data for 106 CHF patients were collated (98 men, age 62 ± 10 yrs, wt 79 ± 14 Kg). Patients were moderately impaired (peak VO216.9 ± 4.4 mls/kg/min), with moderate LV systolic dysfunction (EF 30 ± 6.9%), 78% (83) had ischaemic cardiomyopathy. After ExT, peak VO2increased 1.4 ± 3.4 ml/kg/min (P<.001), serum TNF-alpha decreased 1.9 ± 8.6 pg/ml (P=.02) and IL-6 was not significantly changed (0.5 ± 5.4 pg/ml,P=.32) for the whole group. Baseline and post-training peak VO2changes were not correlated with change in cytokine levels.Conclusions. Exercise training reduces levels TNF-alpha but not IL-6 in CHF. However, across a heterogenic patient group, change in peak VO2was not correlated with alterations in cytokine levels. While greater exercise volume (hours) was superior in improving peak VO2, no particular characteristic of ExT regimes appeared superior in effecting change in serum cytokines.

Differential requirement for A2a and A3 adenosine receptors for the protective effect of inosine in vivo

Blood ◽  
2003 ◽  
Vol 102 (13) ◽  
pp. 4472-4478 ◽  
Author(s):  
Gregorio Gomez ◽  
Michail V. Sitkovsky
Keyword(s):  
Protective Effect ◽  
Adenosine Receptors ◽  
Tissue Damage ◽  
Wild Type ◽  
In Vivo Models ◽  
Inflammatory Conditions ◽  
Severe Liver Damage ◽  
Lung Tissue Damage ◽  
Deficient Mice

AbstractInosine is an endogenous nucleoside with immunosuppressive properties that is known to inhibit the accumulation of proinflammatory cytokines and protect mice from endotoxin-induced inflammation and lung tissue damage. There are no known receptors specific for inosine, but A3 adenosine receptors (A3Rs) have been shown to bind inosine, resulting in mast cell degranulation and increased vascular permeability. The present study specifically addresses the requirement for A2aR and/or A3R for the protective effect of inosine in 2 experimental in vivo models of inflammatory disease. The data show that A3R is essential for protection against ConA-induced fulminant hepatitis since only A3R-expressing mice were protected by inosine whereas wild-type and A2aR-deficient mice exhibited severe liver damage even after administration of inosine. In addition, we show in a model of LPS-induced endotoxemia that inosine protected both A2aR-/- and A3R-/- mice from inflammation, but not A2aA3R double-null mice, indicating that in this model both A2aR and A3R were used by inosine. Thus, we demonstrate that A2a and A3 adenosine receptors are differentially utilized by inosine for the down-regulation of tissue damage under different inflammatory conditions in vivo. (Blood. 2003;102:4472-4478)

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