Effects of Exogenous Interleukin-6 duringPseudomonas aeruginosa Corneal Infection

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.

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Roles of Interleukin‐6 and Macrophage Inflammatory Protein–2 in Pneumolysin‐Induced Lung Inflammation in Mice

The Journal of Infectious Diseases ◽

10.1086/338008 ◽

2002 ◽

Vol 185 (1) ◽

pp. 123-126 ◽

Cited By ~ 49

Author(s):

Anita W. Rijneveld ◽

Germie P. van den Dobbelsteen ◽

Sandrine Florquin ◽

Theodore J. Standiford ◽

Peter Speelman ◽

...

Keyword(s):

Interleukin 6 ◽

Lung Inflammation ◽

Inflammatory Protein ◽

Macrophage Inflammatory Protein

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00300.2003 ◽

2004 ◽

Vol 287 (3) ◽

pp. G734-G741 ◽

Cited By ~ 45

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.

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Potential Role of the Chemokine Macrophage Inflammatory Protein 1α in Human and Experimental Schistosomiasis

Infection and Immunity ◽

10.1128/iai.73.4.2515-2523.2005 ◽

2005 ◽

Vol 73 (4) ◽

pp. 2515-2523 ◽

Cited By ~ 23

Author(s):

Adriano L. S. Souza ◽

Ester Roffê ◽

Vanessa Pinho ◽

Danielle G. Souza ◽

Adriana F. Silva ◽

...

Keyword(s):

Potential Role ◽

Severe Disease ◽

Experimental Studies ◽

Interleukin 4 ◽

Enzyme Linked Immunosorbent Assay ◽

Inflammatory Protein ◽

Macrophage Inflammatory Protein ◽

Deficient Mice

ABSTRACT In human schistosomiasis, the concentrations of the chemokine macrophage inflammatory protein 1α (MIP-1α/CCL3) is greater in the plasma of patients with clinical hepatosplenic disease. The objective of the present study was to confirm the ability of CCL3 to detect severe disease in patients classified by ultrasonography (US) and to evaluate the potential role of CCL3 in Schistosoma mansoni-infected mice. CCL3 was measured by enzyme-linked immunosorbent assay in the plasma of S. mansoni-infected patients. CCL3-deficient mice were infected with 25 cercariae, and various inflammatory and infectious indices were evaluated. The concentration of CCL3 was higher in the plasma of S. mansoni-infected than noninfected patients. Moreover, CCL3 was greater in those with US-defined hepatosplenic than with the intestinal form of the disease. In CCL3-deficient mice, the size of the granuloma and the liver eosinophil peroxidase activity and collagen content were diminished compared to wild-type mice. In CCL3-deficient mice, the worm burden after 14 weeks of infection, but not after 9 weeks, was consistently smaller. The in vitro response of mesenteric lymph node cells to antigen stimulation was characterized by lower levels of interleukin-4 (IL-4) and IL-10. CCL3 is a marker of disease severity in infected humans, and experimental studies in mice suggest that CCL3 may be a causative factor in the development of severe schistosomiasis.

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Fever induced by macrophage inflammatory protein-1β in the rat is independent of hypothalamic interleukin-1β or interleukin-6

Journal of Thermal Biology ◽

10.1016/s0306-4565(99)00036-4 ◽

2000 ◽

Vol 25 (1-2) ◽

pp. 5-10 ◽

Cited By ~ 4

Author(s):

Khalid Benamar ◽

Antonio Fernández-Alonso ◽

Eva Tavares ◽

Francisco J López-Valpuesta ◽

Manuel Sancibrián ◽

...

Keyword(s):

Interleukin 6 ◽

Interleukin 1Β ◽

Inflammatory Protein ◽

Macrophage Inflammatory Protein

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Associations of interleukin-6 with interleukin-1β, interleukin-8 and macrophage inflammatory protein-1β in midlife women

Cytokine ◽

10.1016/j.cyto.2007.12.001 ◽

2008 ◽

Vol 41 (3) ◽

pp. 302-306 ◽

Cited By ~ 13

Author(s):

Toshiyuki Yasui ◽

Hirokazu Uemura ◽

Masayo Yamada ◽

Toshiya Matsuzaki ◽

Naoko Tsuchiya ◽

...

Keyword(s):

Interleukin 6 ◽

Midlife Women ◽

Interleukin 8 ◽

Interleukin 1Β ◽

Inflammatory Protein ◽

Macrophage Inflammatory Protein

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

Infection and Immunity ◽

10.1128/iai.69.10.5991-5996.2001 ◽

2001 ◽

Vol 69 (10) ◽

pp. 5991-5996 ◽

Cited By ~ 62

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.

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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 ◽

10.1182/blood.v96.9.2973.h8002973_2973_2980 ◽

2000 ◽

Vol 96 (9) ◽

pp. 2973-2980 ◽

Cited By ~ 1

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.

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

Infection and Immunity ◽

10.1128/iai.70.9.5177-5184.2002 ◽

2002 ◽

Vol 70 (9) ◽

pp. 5177-5184 ◽

Cited By ~ 38

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.

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

Blood ◽

10.1182/blood-2010-01-266072 ◽

2010 ◽

Vol 116 (11) ◽

pp. 1924-1931 ◽

Cited By ~ 137

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.

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