scholarly journals Fcγ Receptor I- and III-Mediated Macrophage Inflammatory Protein 1α Induction in Primary Human and Murine Microglia

2002 ◽  
Vol 70 (9) ◽  
pp. 5177-5184 ◽  
Author(s):  
Xianyuan Song ◽  
Scott Shapiro ◽  
David L. Goldman ◽  
Arturo Casadevall ◽  
Matthew Scharff ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Neurological Diseases ◽  
Mitogen Activated Protein Kinase ◽  
Pyrrolidine Dithiocarbamate ◽  
Wild Type ◽  
Human Microglia ◽  
Downstream Signaling ◽  
Inflammatory Protein ◽  
Α Chain ◽  
Macrophage Inflammatory Protein

ABSTRACT Microglial cell phagocytic receptors may play important roles in the pathogenesis and treatment of several neurological diseases. We studied microglial Fc receptor (FcR) activation with respect to the specific FcγR types involved and the downstream signaling events by using monoclonal antibody (MAb)-coated Cryptococcus neoformans immune complexes as the stimuli and macrophage inflammatory protein 1α (MIP-1α) production as the final outcome. C. neoformans complexed with murine immunoglobulin G (IgG) of γ1, γ2a, and γ3, but not γ2b isotype, was effective in inducing MIP-1α in human microglia. Since murine γ2b binds to human FcγRII (but not FcγRI or FcγRIII), these results indicate that FcγRI and/or FcγRIII is involved in MIP-1α production. Consistent with this, an antibody that blocks FcγRII (IV.3) failed to inhibit MIP-1α production, while an antibody that blocks FcγRIII (3G8) did. An anti-C. neoformans MAb, 18B7 (IgG1), but not its F(ab′)2, induced extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase kinase phosphorylation, and MIP-1α release was suppressed by the ERK inhibitor U0126. C. neoformans plus 18B7 also induced degradation of I-κBα, and MIP-1α release was suppressed by the antioxidant NF-κB inhibitor pyrrolidine dithiocarbamate. To confirm the role of FcR more directly, we isolated microglia from wild-type and various FcR-deficient mice and then challenged them with C. neoformans plus 18B7. While FcγRII-deficient microglia showed little difference from the wild-type microglia, both FcγRI α-chain- and FcγRIII α-chain-deficient microglia produced less MIP-1α, and the common Fc γ-chain-deficient microglia showed no MIP-1α release. Taken together, our results demonstrate a definitive role for FcγRI and FcγRIII in microglial chemokine induction and implicate ERK and NF-κB as the signaling components leading to MIP-1α expression. Our results delineate a new mechanism for microglial activation and may have implications for central nervous system inflammatory diseases.

scholarly journals Limited role for CXC chemokines in the pathogenesis of α-naphthylisothiocyanate-induced liver injury

2004 ◽  
Vol 287 (3) ◽  
pp. G734-G741 ◽  
Author(s):  
Junquan Xu ◽  
Gene Lee ◽  
Haimei Wang ◽  
John M. Vierling ◽  
Jacquelyn J. Maher
Keyword(s):  
Bile Ducts ◽  
Tissue Injury ◽  
Hepatic Inflammation ◽  
Wild Type ◽  
Hepatocellular Injury ◽  
Neutrophilic Inflammation ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein ◽  
Portal Tracts

α-Naphthylisothiocyanate (ANIT) is a hepatotoxin that causes severe neutrophilic inflammation around portal tracts and bile ducts. The chemotactic signals that provoke this inflammatory response are unknown. In this study, we addressed the possibility that ANIT upregulates CXC chemokines in the liver and that these compounds mediate hepatic inflammation and tissue injury after ANIT treatment. Mice treated with a single dose of ANIT (50 mg/kg) exhibited rapid hepatic induction of the CXC chemokine macrophage inflammatory protein-2 (MIP-2). MIP-2 derived primarily from hepatocytes, with no apparent contribution by biliary cells. In ANIT-treated mice, the induction of MIP-2 coincided with an influx of neutrophils to portal zones; this hepatic neutrophil recruitment was suppressed by 50% in mice that lack the receptor for MIP-2 (CXCR2−/−). Interestingly, despite their markedly reduced degree of hepatic inflammation, CXCR2−/− mice displayed just as much hepatocellular injury and cholestasis after ANIT treatment as wild-type mice. Moreover, after long-term exposure, ANIT CXCR2−/− mice developed liver fibrosis that was indistinguishable from that in wild-type mice. In summary, our data show that CXC chemokines are responsible for some of the hepatic inflammation that occurs in response to ANIT but that these compounds are not essential to the pathogenesis of either acute or chronic ANIT hepatotoxicity.

scholarly journals Effects of Exogenous Interleukin-6 duringPseudomonas aeruginosa Corneal Infection

2001 ◽  
Vol 69 (6) ◽  
pp. 4116-4119 ◽  
Author(s):  
Nerida Cole ◽  
Mark Krockenberger ◽  
Shisan Bao ◽  
Kenneth W. Beagley ◽  
Alan J. Husband ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Gene Knockout ◽  
Severe Disease ◽  
Neutrophil Recruitment ◽  
Wild Type ◽  
Corneal Infection ◽  
Inflammatory Protein ◽  
Cell Adhesion Molecule 1 ◽  
Intercellular Cell Adhesion Molecule ◽  
Macrophage Inflammatory Protein

ABSTRACT Lack of interleukin-6 (IL-6) during Pseudomonas aeruginosa corneal infection leads to more severe disease with changes in neutrophil recruitment. Exogenous IL-6 leads to increased efficiency of neutrophil recruitment and reduced bacterial loads in corneal infection in both IL-6 gene knockout and wild-type mice. This may be mediated by IL-6 increasing the production of corneal macrophage inflammatory protein 2 and intercellular cell adhesion molecule 1. We conclude that effective recruitment of neutrophils into the cornea is dependent on the production of IL-6 and that early augmentation of IL-6 may be protective in corneal infection.

Interleukin-6 and interleukin-11: same same but different

2013 ◽  
Vol 394 (9) ◽  
pp. 1145-1161 ◽  
Author(s):  
Christoph Garbers ◽  
Jürgen Scheller
Keyword(s):  
Neuronal Development ◽  
Inflammatory Diseases ◽  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Cytokine Signaling ◽  
Downstream Signaling ◽  
Mitogen Activated Protein ◽  
Β Receptor ◽  
Redundant Functions

Abstract The pleiotropic physiological functions of interleukin (IL-)6 type cytokines range from embryonic development and tissue homoeostasis to neuronal development and T cell differentiation. In contrast, imbalance of the well-controlled cytokine signaling network leads to chronic inflammatory diseases and cancer. IL-6 and IL-11 both signal through a homodimer of the ubiquitously expressed β-receptor glycoprotein 130 (gp130). Specificity is gained through an individual IL-6/IL-11 α-receptor, which does not directly participate in signal transduction, although the initial cytokine binding event to the α-receptor leads to the final complex formation with the β-receptors. Both cytokines activate the same downstream signaling pathways, which are predominantly the mitogen-activated protein kinase (MAPK)-cascade and the Janus kinase/signal transducer and activator of transcription (Jak/STAT) pathway. However, recent studies have highlighted divergent roles of the two related cytokines. Here, we will discuss how the biochemical similarities are translated into unique and non-redundant functions of IL-6 and IL-11 in vivo and illustrate strategies for cytokine-specific therapeutic intervention.

scholarly journals Impaired Pulmonary NF-κB Activation in Response to Lipopolysaccharide in NADPH Oxidase-Deficient Mice

2001 ◽  
Vol 69 (10) ◽  
pp. 5991-5996 ◽  
Author(s):  
M. Audrey Koay ◽  
John W. Christman ◽  
Brahm H. Segal ◽  
Annapurna Venkatakrishnan ◽  
Thomas R. Blackwell ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Intracellular Signaling ◽  
Lung Inflammation ◽  
Nuclear Translocation ◽  
Binding Activity ◽  
Wild Type ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein ◽  
Deficient Mice

ABSTRACT Reactive oxygen species (ROS) are thought to be involved in intracellular signaling, including activation of the transcription factor NF-κB. We investigated the role of NADPH oxidase in the NF-κB activation pathway by utilizing knockout mice (p47phox−/−) lacking the p47phox component of NADPH oxidase. Wild-type (WT) controls and p47phox−/−mice were treated with intraperitoneal (i.p.) Escherichia coli lipopolysaccharide (LPS) (5 or 20 μg/g of body weight). LPS-induced NF-κB binding activity and accumulation of RelA in nuclear protein extracts of lung tissue were markedly increased in WT compared to p47phox−/− mice 90 min after treatment with 20 but not 5 μg of i.p. LPS per g. In another model of lung inflammation, RelA nuclear translocation was reduced in p47phox−/− mice compared to WT mice following treatment with aerosolized LPS. In contrast to NF-κB activation in p47phox−/− mice, LPS-induced production of macrophage inflammatory protein 2 in the lungs and neutrophilic lung inflammation were not diminished in these mice compared to WT mice. We conclude that LPS-induced NF-κB activation is deficient in the lungs of p47phox−/− mice compared to WT mice, but this abnormality does not result in overt alteration in the acute inflammatory response.

T-lymphocyte production of macrophage inflammatory protein-1α is critical to the recruitment of CD8+ T cells to the liver, lung, and spleen during graft-versus-host disease

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 2973-2980 ◽  
Author(s):  
Jonathan S. Serody ◽  
Susan E. Burkett ◽  
Angela Panoskaltsis-Mortari ◽  
Judith Ng-Cashin ◽  
Eileen McMahon ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Class I ◽  
Wild Type ◽  
Host Disease ◽  
Graft Versus Host ◽  
Inflammatory Protein ◽  
Donor T Cells ◽  
Macrophage Inflammatory Protein

To investigate the mechanism by which macrophage inflammatory protein-1α (MIP-1α) affects graft-versus-host disease (GVHD), the expression and function of MIP-1α in 2 murine models of GVHD were evaluated. In irradiated class I and class II disparate recipients, the expression of messenger RNA (mRNA) and protein for MIP-1α was significantly increased in GVHD target organs after transfer of allogeneic lymphocytes compared to syngeneic lymphocytes. When lymphocytes unable to make MIP-1α were transferred, there was a decrease in the production of MIP-1α in the liver, lung, and spleen of bm1 (B6.C-H2bm1/By) and bm12 (B6.C-H2bm12/KhEg) recipients compared to the transfer of wild-type splenocytes. At day 6 there was a 4-fold decrease in the number of transferred CD8+ T cells in the lung and approximately a 2-fold decrease in the number of CD8+ T cells in the liver and spleen in bm1 recipients after transfer of MIP-1α–deficient (MIP-1α−/−) splenocytes compared to wild-type (MIP-1α+/+) splenocytes. These differences persisted for 13 days after splenocyte transfer. In contrast, the number of donor CD4+ T cells found in the liver and lung was significantly increased after the transfer of MIP-1α−/− compared to wild-type splenocytes in bm12 recipients from day 6 through day 10. Thus, the transfer of allogeneic T cells was associated with the enhanced expression of MIP-1α in both a class I and class II mismatch setting. However, the increased expression only led to enhanced recruitment of CD8+, but not CD4+, donor T cells. Production of MIP-1α by donor T cells is important in the occurrence of GVHD and functions in a tissue-dependent fashion.

scholarly journals Macrophage Inflammatory Protein-1β Induces Migration and Activation of Human Thymocytes

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2905-2913 ◽  
Author(s):  
Daniel J. Dairaghi ◽  
Karin Franz-Bacon ◽  
Eleni Callas ◽  
James Cupp ◽  
Thomas J. Schall ◽  
...  
Keyword(s):  
Radioligand Binding ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Double Positive ◽  
Migratory Activity ◽  
Inflammatory Protein ◽  
Mitogen Activated Protein ◽  
Single Positive ◽  
Nih 3T3 ◽  
Macrophage Inflammatory Protein

The CC chemokine macrophage inflammatory protein 1β (MIP-1β), has been shown to be a chemoattractant preferentially activating CD4+ CD45RA+ T lymphocytes. Further analysis of chemokine action on lymphocytic cells has shown the potent migration-promoting capacity of MIP-1β on human thymocytes. The responding cells were the CD4+ and CD8+single-positive (SP), as well as the CD4+CD8+ double-positive (DP) populations, with little if any migratory activity on the double-negative (DN) population. The activation of thymocytes by MIP-1β appeared to be a direct, receptor-mediated event as evidenced by the rapid mobilization of intracellular calcium, increase in proteins phosphorylated on tyrosine, and activation of the mitogen-activated protein kinase (MAPK) pathway. Radioligand binding analyses showed specific and displaceable binding of MIP-1β to thymocytes with a Kd of approximately 1 nmol/L, a profile that was comparable with MIP-1β binding to CCR-5–transfected NIH 3T3 cells. In addition, CCR-5 mRNA was detected in total thymocyte populations indicating that activation of thymocytes by MIP-1β may occur through binding to CCR-5. Further dissection of the subpopulations showed that only the DP and CD8+ SP populations expressed CCR-5 and expression data on these two populations was confirmed using anti–CCR-5 monoclonal antibody. These data may be suggestive of a role for MIP-1β in human thymocyte activation, and show a potential route for HIV infectivity in the developing immune system.

Acid-induced Lung Injury

2003 ◽  
Vol 99 (6) ◽  
pp. 1323-1332 ◽  
Author(s):  
Lilly Madjdpour ◽  
Sita Kneller ◽  
Christa Booy ◽  
Thomas Pasch ◽  
Ralph C. Schimmer ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Expression Pattern ◽  
Binding Activity ◽  
Pyrrolidine Dithiocarbamate ◽  
Inflammatory Protein ◽  
Nf Kappab ◽  
Macrophage Inflammatory Protein

Background Aspiration of acidic gastric contents leads to acute lung injury and is still one of the most common clinical events associated with acute lung injury. This study was performed to assess acid-induced lung inflammation in vitro and in vivo with respect to the time pattern of activated transcription factor nuclear factor-kappaB (NF-kappaB) and proinflammatory molecules. Methods L2 cells (alveolar epithelial cells) were exposed for various periods to a medium with a pH of 6. In the in vivo model, 1 ml/kg of 0.1 n acidic solution was instilled into the lungs of rats. NF-kappaB binding activity and expression pattern of inflammatory mediators were determined. Blocking studies were performed with the NF-kappaB inhibitor pyrrolidine dithiocarbamate. Results In vitro NF-kappaB binding activity showed a biphasic expression pattern with a first peak at 1 h and a second one at 6-8 h. In acid-injured rat lungs, NF-kappaB binding activity was confirmed in a biphasic manner with a first increase at 0.5-2 h (608 +/- 93% and 500 +/- 15%, respectively, P < 0.05) and a second peak at 8 h (697 +/- 35% increase, P < 0.005). Whole lung mRNA for macrophage inflammatory protein-1beta and macrophage inflammatory protein-2 showed a similar expression pattern, which could explain the biphasic neutrophil recruitment. Intratracheal pyrrolidine dithiocarbamate attenuated lung injury as evidenced by a reduction of neutrophil accumulation and expression of inflammatory mediators. Conclusions These data suggest that NF-kappaB binding activity plays a key role in molecular and cellular events in acid-induced lung injury.

scholarly journals A chemotactic gradient sequestered on endothelial heparan sulfate induces directional intraluminal crawling of neutrophils

Blood ◽  
2010 ◽  
Vol 116 (11) ◽  
pp. 1924-1931 ◽  
Author(s):  
Sara Massena ◽  
Gustaf Christoffersson ◽  
Elina Hjertström ◽  
Eyal Zcharia ◽  
Israel Vlodavsky ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Bacterial Infections ◽  
Target Tissue ◽  
Infection Site ◽  
Wild Type ◽  
Inflammatory Protein ◽  
Chemokine Gradient ◽  
Macrophage Inflammatory Protein ◽  
Chemotactic Gradient

Abstract During infection, chemokines sequestered on endothelium induce recruitment of circulating leukocytes into the tissue where they chemotax along chemokine gradients toward the afflicted site. The aim of this in vivo study was to determine whether a chemokine gradient was formed intravascularly and influenced intraluminal neutrophil crawling and transmigration. A chemokine gradient was induced by placing a macrophage inflammatory protein-2 (MIP-2)–containing (CXCL2) gel on the cremaster muscle of anesthetized wild-type mice or heparanase-overexpressing transgenic mice (hpa-tg) with truncated heparan sulfate (HS) side chains. Neutrophil-endothelial interactions were visualized by intravital microscopy and chemokine gradients detected by confocal microscopy. Localized extravascular chemokine release (MIP-2 gel) induced directed neutrophil crawling along a chemotactic gradient immobilized on the endothelium and accelerated their recruitment into the target tissue compared with homogeneous extravascular chemokine concentration (MIP-2 superfusion). Endothelial chemokine sequestration occurred exclusively in venules and was HS-dependent, and neutrophils in hpa-tg mice exhibited random crawling. Despite similar numbers of adherent neutrophils in hpa-tg and wild-type mice, the altered crawling in hpa-tg mice was translated into decreased number of emigrated neutrophils and ultimately decreased the ability to clear bacterial infections. In conclusion, an intravascular chemokine gradient sequestered by endothelial HS effectively directs crawling leukocytes toward transmigration loci close to the infection site.

scholarly journals H-Ras Signaling and K-Ras Signaling Are Differentially Dependent on Endocytosis

2002 ◽  
Vol 22 (14) ◽  
pp. 5128-5140 ◽  
Author(s):  
Sandrine Roy ◽  
Bruce Wyse ◽  
John F. Hancock
Keyword(s):  
Plasma Membrane ◽  
Specific Activity ◽  
Mitogen Activated Protein Kinase ◽  
Membrane Microdomains ◽  
Ras Signaling ◽  
Wild Type ◽  
Endocytic Recycling ◽  
Membrane Recruitment ◽  
Downstream Signaling ◽  
Mitogen Activated Protein

ABSTRACT Endocytosis is required for efficient mitogen-activated protein kinase (MAPK) activation by activated growth factor receptors. We examined if H-Ras and K-Ras proteins, which are distributed across different plasma membrane microdomains, have equal access to the endocytic compartment and whether this access is necessary for downstream signaling. Inhibition of endocytosis by dominant interfering dynamin-K44A blocked H-Ras but not K-Ras-mediated PC12 cell differentiation and selectively inhibited H-Ras- but not K-Ras-mediated Raf-1 activation in BHK cells. H-Ras- but not K-Ras-mediated Raf-1 activation was also selectively dependent on phosphoinositide 3-kinase activity. Stimulation of endocytosis and endocytic recycling by wild-type Rab5 potentiated H-Ras-mediated Raf-1 activation. In contrast, Rab5-Q79L, which stimulates endocytosis but not endocytic recycling, redistributed activated H-Ras from the plasma membrane into enlarged endosomes and inhibited H-Ras-mediated Raf-1 activation. Rab5-Q79L expression did not cause the accumulation of wild-type H-Ras in enlarged endosomes. Expression of wild-type Rab5 or Rab5-Q79L increased the specific activity of K-Ras-activated Raf-1 but did not result in any redistribution of K-Ras from the plasma membrane to endosomes. These results show that H-Ras but not K-Ras signaling though the Raf/MEK/MAPK cascade requires endocytosis and endocytic recycling. The data also suggest a mechanism for returning Raf-1 to the cytosol after plasma membrane recruitment.

Sign in / Sign up

Export Citation Format

Share Document