Increased Susceptibility to LPS-induced Endotoxin Shock in Secretory Leukoprotease Inhibitor (SLPI)-deficient Mice

Nakamura, Akira; Mori, Yuriko; Hagiwara, Koichi; Suzuki, Takuji; Sakakibara, Tomohiro; Kikuchi, Toshiaki; Igarashi, Tadashi; Ebina, Masahito; Abé, Tatsuya; Miyazaki, Jun‐ichi; Takai, Toshiyuki; Nukiwa, Toshihiro

doi:10.1084/jem.20021824

Cited by 125 publications

(105 citation statements)

References 22 publications

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“…Consistently, it has been shown more recently that ALP-deficient mice have increased mortality in response to LPS-induced shock, and that ALP-deficient macrophages show higher interleukin-6 and NF-B activities upon LPS challenge compared with macrophages from wild-type mice (33). However, the underlying immune complex-dependent pathology in antibody transferinduced arthritis has provoked a different focus on the antiinflammatory effects of ALP and has finally led to the detection of new facets of action in the present investigations.…”

Section: Discussionsupporting

confidence: 51%

Antileukoproteinase: Modulation of neutrophil function and therapeutic effects on anti–type II collagen antibody–induced arthritis

Sehnert¹,

Cavcic²,

Böhm³

et al. 2004

Arthritis & Rheumatism

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Objective. Antileukoproteinase (ALP) is a physiologic inhibitor of granulocytic serine proteases. The present study was undertaken to investigate its therapeutic benefit in an antibody-transfer model of erosive polyarthritis and to elucidate its potential to interfere with immune complex-dependent inflammatory pathways.Methods. Arthritis development was induced in male (BALB/c ؋ B10.Q)F 1 mice by intravenous injection of two monoclonal antibodies specific for type II collagen and was quantified by clinical scoring and histopathology. Arthritis severity was assessed in a cohort of mice under systemic treatment with recombinant human ALP (daily doses of 0.1 mg for 5 days starting immediately after disease induction) in comparison with untreated controls. Concomitantly, functional assays (phagocytosis, oxidative burst, fluorescence-activated cell sorting analysis of integrin expression) were performed on neutrophils upon in vitro stimulation by IgG-coated latex beads.Results. ALP treatment reduced arthritis incidence and severity and had a protective effect against cartilage and bone erosion. ALP inhibited the conversion of the leukocyte ␤2 integrins into an active conformation upon Fc receptor stimulation of granulocytes. ALP bound to the actin-bundling protein L-plastin and down-modulated filamentous actin assembly in response to stimulation with IgG-coated latex beads in granulocytes. ALP exerted additional inhibitory effects on neutrophil functions associated with cytoskeletal reorganization, such as phagocytosis and oxidative burst.Conclusion. In addition to its antiprotease activity, ALP exerts a variety of blocking effects on neutrophil functions, probably due to modulation of cytoskeletal changes, that may contribute to this inhibitor's antiarthritis potential and qualify it as a multifunctional regulator of inflammatory responses.Antileukoproteinase (ALP), also named secretory leukocyte protease inhibitor for its presence in epithelial secretions and its ability to inhibit neutrophil serine protease, is a highly basic, acid-stable polypeptide. It comprises two mutually homologous highly disulfidebonded domains connected by a short linker (1). ALP circulates in blood, and experimental evidence indicates its physiologic expression by a variety of mucosal epithelial cells, by neutrophils (2), and by murine, but not human, macrophages (3). However, its low molecular weight (11 kd) and its cationic nature (pI Ͼ10) predispose ALP to leaving the circulation for specific accumulation in tissues, especially in cartilage (4,5).In addition to its antiproteolytic properties, ALP has been shown to exert a variety of antiinflammatory actions on macrophages and neutrophils (e.g., the suppression of lipopolysaccharide [LPS]-induced prostaglandin E 2 and matrix metalloproteinase production or

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Section: Discussionsupporting

confidence: 51%

Antileukoproteinase: Modulation of neutrophil function and therapeutic effects on anti–type II collagen antibody–induced arthritis

Sehnert¹,

Cavcic²,

Böhm³

et al. 2004

Arthritis & Rheumatism

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“…In other studies, SLPI-deficient mice were reported to be more sensitive to LPS-induced shock; their macrophages had higher IL-6 and NF-kB activity, suggesting that SLPI attenuates excessive inflammatory responses. 49 Taggart, Greene, and co-workers 50,51 demonstrated that SLPI downregulates TNF-α expression induced by LPS by inhibiting degradation of IkBp and binds directly to NF-kB in a site-specific manner. More recently, E 2 was found to protect against Human Immunodeficiency Virus Tat protein-induced inflammatory reactions in vascular endothelium by blocking NF-kB signaling.…”

Section: Discussionmentioning

confidence: 99%

Estradiol selectively regulates innate immune function by polarized human uterine epithelial cells in culture

et al. 2008

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The goal of this study was to examine the role of E 2 in regulating innate immune protection by human uterine epithelial cells (UECs). Recognizing that UECs produce cytokines and chemokines to recruit and activate immune cells as well as viral and bacterial antimicrobials, we sought to examine the effect of E 2 on constitutive and Toll-like receptor (TLR) agonist (lipopolysaccharide (LPS) and poly (I:C))-induced immune responses. The secretion by polarized UECs in culture of interleukin (IL)-6, macrophage inhibitory factor (MIF), and secretory leukocyte protease inhibitor (SLPI) was examined as well as the mRNA expression of human β-defensin-2 (HBD2), tumor necrosis factor (TNF)-α, IL-8, and nuclear factor (NF)-kB. When incubated with E 2 for 24-48 h, we found that E 2 stimulated UEC secretion of SLPI (fourfold) and mRNA expression of HBD2 (fivefold). Moreover, when antibacterial activity in UEC secretions was measured using Staphylococcus aureus, E 2 increased the secretion of soluble factor(s) with antibacterial activity. In contrast, E 2 had no effect on constitutive secretion of proinflammatory cytokines and chemokines by UECs but completely inhibited LPS-and poly (I:C)-induced secretion of MIF, IL-6, and IL-8. Estradiol also reversed the stimulatory effects of IL-1β on mRNA expression of TNF-α, IL-8, and NF-kB by 85, 95, and 70%, respectively. As SLPI is known to inhibit NF-kB expression, these findings suggest that E 2 inhibition of proinflammatory cytokines may be mediated through SLPI regulation of NF-kB. Overall, these findings indicate that the production of cytokines, chemokines, and antimicrobials by UECs are differentially regulated by E 2 . Further, it suggests that with E 2 regulation, epithelial cells that line the uterine cavity have evolved immunologically to be sensitive to viral and bacterial infections as well as the constraints of procreation.

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“…Depending on the mouse strain, the source of endotoxin, and the cytokine assays used, considerable variations in the cytokine response were reported (1,14,22,24). TNF-␣ levels peaked 1 h after LPS injection and ranged from 100 pg/ml (22) to 600 pg/ml (1) to 15,000 pg/ml (14). Reported serum IL-6 levels peaked between 2 and 4 h after LPS injection and ranged from 900 pg/ml (1) to 5,000 pg/ml (14) to 40,000 pg/ml (24).…”

Section: Discussionmentioning

confidence: 99%

Therapy of Experimental Pseudomonas Infections with a Nonreplicating Genetically Modified Phage

Hagens

Habel

Ahsen

et al. 2004

Antimicrob Agents Chemother

168

111

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Bacteriophage therapy of bacterial infections has received renewed attention owing to the increasing prevalence of antibiotic-resistant pathogens. A side effect of many antibiotics as well as of phage therapy with lytic phage is the release of cell wall components, e.g., endotoxins of gram-negative bacteria, which mediate the general pathological aspects of septicemia. Here we explored an alternative strategy by using genetically engineered nonreplicating, nonlytic phage to combat an experimental Pseudomonas aeruginosa infection. An export protein gene of the P. aeruginosa filamentous phage Pf3 was replaced with a restriction endonuclease gene. This rendered the Pf3 variant (Pf3R) nonreplicative and concomitantly prevented the release of the therapeutic agent from the target cell. The Pf3R phage efficiently killed a wild-type host in vitro, while endotoxin release was kept to a minimum. Treatment of P. aeruginosa infections of mice with Pf3R or with a replicating lytic phage resulted in comparable survival rates upon challenge with a minimal lethal dose of 3. However, the survival rate after phage therapy with Pf3R was significantly higher than that with the lytic phage upon challenge with a minimal lethal dose of 5. This higher survival rate correlated with a reduced inflammatory response elicited by Pf3R treatment relative to that with the lytic phage. Therefore, this study suggests that the increased survival rate of Pf3R-treated mice could result from reduced endotoxin release. Thus, the use of a nonreplicating modified phage for the delivery of genes encoding proteins toxic to bacterial pathogens may open up a new avenue in antimicrobial therapy.

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Increased Susceptibility to LPS-induced Endotoxin Shock in Secretory Leukoprotease Inhibitor (SLPI)-deficient Mice

Cited by 125 publications

References 22 publications

Antileukoproteinase: Modulation of neutrophil function and therapeutic effects on anti–type II collagen antibody–induced arthritis

Antileukoproteinase: Modulation of neutrophil function and therapeutic effects on anti–type II collagen antibody–induced arthritis

Estradiol selectively regulates innate immune function by polarized human uterine epithelial cells in culture

Therapy of Experimental Pseudomonas Infections with a Nonreplicating Genetically Modified Phage

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