interleukin-8 and Leukocyte-Disorders

Type B acute aortic dissection (AAD) spares the ascending aorta and is optimally managed by medical therapy in the absence of complications. However, patients with enhanced inflammation sometimes present with aortic enlargement, thereby facing undesirable outcomes. Thus, a better understanding of the molecular and cellular mechanisms involved in AAD-associated inflammatory processes and the requirement for a novel therapeutic approach for patients with type B AAD are unmet clinical needs. This study showed that dissection per se induced neutrophil-chemoattractant chemokine expression in the aortic tunica adventitia, possibly by mechanical injury and stretching followed by pseudolumen formation. Subsequent systemic changes in chemokine-dependent signaling caused neutrophilia and massive neutrophil accumulation in the dissected aorta, thereby leading to aortic enlargement and rupture via interleukin-6 production. Importantly, temporal and spatial dynamics of inflammatory cytokine and chemokine elevation, as well as leukocyte recruitment, were consistent between rodents and humans. Our study provides a new mechanistic insight into neutrophil-mediated adventitial inflammation after AAD and implicates CXCR2- or interleukin-6 neutralization as novel therapeutic strategies to prevent large-artery complications, including aneurysm formation and rupture, in patients with type B AAD.

Topics: Acute Disease; Angiotensin II; Animals; Aorta; Aortic Aneurysm; Aortic Dissection; Chemokines; Gene Expression; Humans; Immune System Diseases; Interleukin-6; Interleukin-8; Leukocyte Disorders; Mice; Molecular Targeted Therapy; Neutrophils; Receptors, Interleukin-8B; Systemic Inflammatory Response Syndrome

Topics: Allergy and Immunology; Animals; Carcinogenesis; History, 20th Century; History, 21st Century; Humans; Immune System Diseases; Interleukin-1; Interleukin-8; Leukocyte Disorders; Neoplasms; Signal Transduction; Tumor Necrosis Factor-alpha

Topics: Amino Acid Sequence; Cells, Cultured; Humans; Immune System Diseases; Immunity; Immunity, Innate; Interleukin-1; Interleukin-8; Leukocyte Disorders; Lipopolysaccharides; Monocytes; Neutrophils; Peptides; Tumor Necrosis Factor-alpha

Chemokine receptors CXCR1 and CXCR2 are conserved between guinea pigs and humans, but the distinct role of each receptor in chemotactic responses of neutrophils against chemokine ligands has not been elucidated due in part to the lack of specific inhibitors against these receptors in guinea pigs. In this study, we investigated the roles of guinea pig CXCR1 and CXCR2 on neutrophils in chemotactic responses to guinea pig interleukin (IL)-8 and growth-regulated oncogene (GRO)α by using specific inhibitory antibodies against these receptors. Neutrophil migration induced by IL-8 was partially inhibited by either anti-CXCR1 antibody or anti-CXCR2 antibody. In addition, the migration was inhibited completely when both anti-CXCR1 and anti-CXCR2 antibodies were combined. On the other hand, neutrophil migration induced by GROα was not inhibited by anti-CXCR1 antibody while inhibited profoundly by anti-CXCR2 antibody. These results indicated that CXCR1 and CXCR2 mediated migration induced by the IL-8 synergistically and only CXCR2 mediated migration induced by GROα in guinea pig neutrophils. Our findings on ligand selectivity of CXCR1 and CXCR2 in guinea pigs are consistent with those in humans.

Topics: Animals; Antibodies, Blocking; Cell Movement; Chemokine CXCL1; Chemotaxis; Female; Guinea Pigs; Immune System Diseases; Interleukin-8; Leukocyte Disorders; Neutrophils; Receptors, Interleukin-8A; Receptors, Interleukin-8B

Immunosenescence is the functional deterioration of the immune system during natural aging. Despite increased susceptibility to bacterial infections in older adults, age-associated changes to neutrophil responses are only partially understood, and neutrophil migration has not been characterized in detail. Here we describe reduced chemotaxis but preserved chemokinesis toward a range of inflammatory stimuli in migrating neutrophils isolated from healthy older subjects. Cross-sectional data indicate that migratory behavior changes in the sixth decade of life. Crucially, aberrant migration may increase "bystander" tissue damage and heighten inflammation as a result of excess proteinase release during inaccurate chemotaxis, as well as reducing pathogen clearance. We show evidence of increased neutrophil proteinase activity in older adults, namely, raised levels of neutrophil proteinase substrate-derived peptides and evidence of primary granule release, associated with increased systemic inflammation. Inaccurate migration was causally associated with increased constitutive phosphoinositide 3-kinase (PI3K) signaling; untreated neutrophils from old donors demonstrated significant PI3K activation compared with cells from young donors. PI3K-blocking strategies, specifically inhibition of PI3Kγ or PI3Kδ, restored neutrophil migratory accuracy, whereas SHIP1 inhibition worsened migratory flaws. Targeting PI3K signaling may therefore offer a new strategy in improving neutrophil functions during infections and reduce inappropriate inflammation in older patients.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Aging; Cell Degranulation; Chemotaxis, Leukocyte; Cross-Sectional Studies; Cytokines; Enzyme Activation; Humans; Immune System Diseases; Interleukin-8; Leukocyte Disorders; Middle Aged; Myeloblastin; Neutrophils; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Receptors, Cytokine; Signal Transduction; Young Adult

To investigate the mechanisms affecting neutrophil migration capacity in breast cancer patients before and after chemotherapy.. Peripheral venous blood was collected at the time of diagnosis and immediately prior to the 4th cycle of an anthracycline-based chemotherapy regimen for patients diagnosed with different stages of breast cancer (n = 30), for experimental assays. Blood samples were also collected from a healthy control group (n = 17).. IL-8 serum concentrations were higher in the patient group than in the control group (p = 0.02), and chemotherapy did not further affect this increase. Levels of TNF-α, IL-6, and IL-10 did not differ between controls and patients, or in relation to chemotherapy. Serum levels of nitric oxide (NO) metabolites were elevated following chemotherapy compared to levels detected prior to treatment (p = 0.01). When the supernatants of lipopolysaccharide-stimulated mononuclear cells and neutrophils obtained from the patients were assayed for levels of nitrite, these levels were significantly higher and unchanged, respectively, compared with controls. Expression levels of the chemokine receptors, CXCR1 and CXCR2, were significantly reduced in patients compared to controls, and chemotherapy did not further affect these differences. Furthermore, filamentous actin content for IL-8-activated neutrophils was reduced with chemotherapy (median 8.85; range 3.38-13.43) compared to the content detected prior to treatment (median 9.23; range 2.86-22.16) (p = 0.001).. Elevated systemic levels of IL-8 and NO, desensitization to CXCR activation, and reduction in actin polymerization may affect neutrophil motility in patients before and after chemotherapy.

Topics: Actins; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Case-Control Studies; Cell Movement; Cyclophosphamide; Cytokines; Doxorubicin; Epirubicin; Female; Fluorouracil; Humans; Immune System Diseases; Interleukin-8; Leukocyte Disorders; Middle Aged; Neutrophils; Nitric Oxide; Receptors, CXCR

Several emerging lines of evidence support an anti-inflammatory role for nicotinic acid (niacin); however, its role in the regulation of leukocyte migration in response to inflammatory stimuli has not been elucidated until now. Herein, we have examined the effect of nicotinic acid on neutrophil recruitment in experimentally induced inflammation. We demonstrated that nicotinic acid treatment inhibited interleukin (IL)-8-induced, leukotriene (LT)B4-induced, and carrageenan-induced neutrophil migration into the pleural cavity of BALB/c mice and reduced neutrophil rolling and adherence in a mouse cremaster muscle preparation. Surprisingly, nicotinic acid treatment increased the level of the neutrophil chemoattractant KC in response to carrageenan. These results suggest that nicotinic acid plays an important role in the regulation of inflammation due to its ability to inhibit the actions of the neutrophil chemoattractants IL-8 and LTB4. Further inhibition of chemoattractants leads to impairment of leukocyte rolling and adherence to the vascular endothelium in the microcirculation of inflamed tissues.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Cell Adhesion; Chemokine CXCL1; Disease Models, Animal; Immune System Diseases; Inflammation; Interleukin-8; Leukocyte Disorders; Leukocyte Rolling; Leukotriene B4; Male; Mice; Mice, Inbred BALB C; Neutrophil Infiltration; Niacin; Pleural Cavity

It is well known that neutrophils play very important roles in the development of rheumatoid arthritis (RA) and interleukin (IL)-8 is a critical chemokine in promoting neutrophil migration. We previously showed that increased production of Cyr61 by fibroblast-like synoviocytes (FLS) in RA promotes FLS proliferation and Th17 cell differentiation, thus Cyr61 is a pro-inflammatory factor in RA pathogenesis. In this study, we explored the role of Cyr61 in neutrophil migration to the joints of RA patients.. RA FLS were treated with Cyr61 and IL-8 expression was analyzed by real-time PCR and ELISA. The migration of neutrophils recruited by the culture supernatants was determined by the use of a chemotaxis assay. Mice with collagen-induced arthritis (CIA) were treated with anti-Cyr61 monoclonal antibodies (mAb), or IgG1 as a control. Arthritis severity was determined by visual examination of the paws and joint destruction was determined by hematoxylin-eosin (H&E) staining. Signal transduction pathways in Cyr61-induced IL-8 production were investigated by real-time PCR, western blotting, confocal microscopy, luciferase reporter assay or chromatin immunoprecipitation (ChIP) assay.. We found that Cyr61 induced IL-8 production by RA FLS in an IL-1β and TNF-α independent pathway. Moreover, we identified that Cyr61-induced IL-8-mediated neutrophil migration in vitro. Using a CIA animal model, we found that treatment with anti-Cyr61 mAb led to a reduction in MIP-2 (a counterpart of human IL-8) expression and decrease in neutrophil infiltration, which is consistent with an attenuation of inflammation in vivo. Mechanistically, we showed that Cyr61 induced IL-8 production in FLS via AKT, JNK and ERK1/2-dependent AP-1, C/EBPβ and NF-κB signaling pathways.. Our results here reveal a novel role of Cyr61 in the pathogenesis of RA. It promotes neutrophil infiltration via up-regulation of IL-8 production in FLS. Taken together with our previous work, this study provides further evidence that Cyr61 plays a key role in the vicious cycle formed by the interaction between infiltrating neutrophils, proliferated FLS and activated Th17 cells in the development of RA.

Topics: Adult; Aged; Aged, 80 and over; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Blotting, Western; Chromatin Immunoprecipitation; Cysteine-Rich Protein 61; Enzyme-Linked Immunosorbent Assay; Female; Fibroblasts; Flow Cytometry; Humans; Immune System Diseases; Interleukin-8; Leukocyte Disorders; Male; Mice; Mice, Inbred DBA; Microscopy, Confocal; Middle Aged; Neutrophil Infiltration; Real-Time Polymerase Chain Reaction; Synovial Membrane