Expression of Interleukin (IL)-18 and Functional IL-18 Receptor on Human Vascular Endothelial Cells, Smooth Muscle Cells, and Macrophages

Gerdes, Norbert; Sukhova, Galina K.; Libby, Peter; Reynolds, Rebecca; Young, James L.; Schönbeck, Uwe

doi:10.1084/jem.20011022

Cited by 464 publications

(367 citation statements)

References 49 publications

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“…The neutrophil protein CAP-37 induced expression of intercellular adhesion molecule-1 by SMC (Gonzalez et al, 2004). IL-18 and angiotensin II, agents involved in atherosclerosis, activated MAP kinase and NF-κB signaling in vascular SMC, resulting in enhanced expression of IL-6, IL-8 and MCP-1 gene expression and increased functional IL-18 receptor activity (Gerdes et al, 2002;Sahar et al, 2005). Aβ induced secretion of IL-6 and induced matrix metalloproteinase-2 (MMP-2) activity in HCSMC; this proinflammatory effect could be inhibited by the anti-inflammatory agent dexamethasone (Previti et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Human postmortem brain-derived cerebrovascular smooth muscle cells express all genes of the classical complement pathway: A potential mechanism for vascular damage in cerebral amyloid angiopathy and Alzheimer's disease

Walker

Dalsing-Hernandez

Lue

2008

Microvascular Research

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Deposition of amyloid around blood vessels, known as cerebral amyloid angiopathy (CAA), is a major pathological feature found in the majority of Alzheimer's disease (AD) cases, and activated complement fragments have been detected on CAA deposits in AD brains. In this study, we demonstrate for the first time that human cerebrovascular smooth muscle cells (HCSMC) isolated from cortical vessels derived from postmortem brains can express mRNAs for complement genes C1qB, C1r, C1s, C2, C3, C4, C5, C6, C7, C8 and C9, the components of the classical complement pathway. Secretion of the corresponding complement proteins for these genes was also demonstrated, except for C1q and C5. Of particular significance was the observation that treatment of HCSMC with aggregated amyloid beta (Aβ)1-42 increased expression of complement C3 mRNA and increased release of C3 protein. Aβ treatment of HCSMC also increased expression of C6 mRNA. Interferon-γ induced expression and release of complement C1r, C1s, C2 and C4. As HCSMC are closely associated with Aβ deposits in vessels in the brain, their production of complement proteins could amplify the proinflammatory effects of amyloid in the perivascular environment, further compromising brain vascular integrity.

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Section: Discussionmentioning

confidence: 99%

Human postmortem brain-derived cerebrovascular smooth muscle cells express all genes of the classical complement pathway: A potential mechanism for vascular damage in cerebral amyloid angiopathy and Alzheimer's disease

Walker

Dalsing-Hernandez

Lue

2008

Microvascular Research

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“…A function of IL-18 as another molecule requiring MyD88 for signaling is rather unlikely, since the IL-18 receptor is predominantly expressed on Th1 cells, whereas a prolonged treatment with e.g. IL-18 plus IL-12 is required for stronger expression in monocytic cells (69,70). The ability of GAS to induce MyD88-dependent signaling independently of TLR2/4/9 may not be unique, since other Gram-positive pathogens have been reported to initiate inflammatory responses in the absence of multiple TLRs.…”

Section: Discussionmentioning

confidence: 99%

Group A Streptococcus Activates Type I Interferon Production and MyD88-dependent Signaling without Involvement of TLR2, TLR4, and TLR9

Gratz

Siller

Schaljo

et al. 2008

Journal of Biological Chemistry

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Bacterial pathogens are recognized by the innate immune system through pattern recognition receptors, such as Toll-like receptors (TLRs). Engagement of TLRs triggers signaling cascades that launch innate immune responses. Activation ofMAPKs and NF-B, elements of the major signaling pathways induced by TLRs, depends in most cases on the adaptor molecule MyD88. In addition, Gram-negative or intracellular bacteria elicit MyD88-independent signaling that results in production of type I interferon (IFN). Here we show that in mouse macrophages, the activation of MyD88-dependent signaling by the extracellular Gram-positive human pathogen group A streptococcus (GAS; Streptococcus pyogenes) does not require TLR2, a receptor implicated in sensing of Gram-positive bacteria, or TLR4 and TLR9. Redundant engagement of either of these TLR molecules was excluded by using TLR2/4/9 triple-deficient macrophages. We further demonstrate that infection of macrophages by GAS causes IRF3 (interferon-regulatory factor 3)-dependent, MyD88-independent production of IFN. Surprisingly, IFN is induced also by GAS lacking slo and sagA, the genes encoding cytolysins that were shown to be required for IFN production in response to other Gram-positive bacteria. Our data indicate that (i) GAS is recognized by a MyD88-dependent receptor other than any of those typically used by bacteria, and (ii) GAS as well as GAS mutants lacking cytolysin genes induce type I IFN production by similar mechanisms as bacteria requiring cytoplasmic escape and the function of cytolysins.Group A streptococcus (GAS 4 ; Streptococcus pyogenes) is an important human Gram-positive pathogen responsible for a wide spectrum of infections, ranging from mild diseases (e.g. tonsillitis) to serious illness (e.g. necrotizing fasciitis, sepsis, or severe poststreptococcal sequelae) (1). The persistence of GAS in the human population and the severity of some GAS diseases are the result of activities of a number of virulence factors that enable the pathogen to escape immune surveillance or, on contrary, induce an overreaction of the immune system (2, 3). Although GAS is generally regarded as an extracellular pathogen, recent findings suggest that GAS can survive (although not multiply) within various host cells, such as neutrophils, macrophages, epithelial cells, and fibroblasts (4 -7). The surviving bacteria may serve as a reservoir for recurrent GAS diseases.Immune responses to bacteria are initiated by recognition of bacterial components called pathogen-associated molecular patterns through host cell-encoded pattern recognition receptors (PRRs) (8, 9). Typically, pathogen-associated molecular patterns are components of the bacterial cell wall (e.g. lipopolysaccharide and lipoteichoic acid), but they may also be derived from the inside of bacteria (e.g. DNA). The primary function of PRRs is to trigger signaling cascades that activate antimicrobial defense programs. The best studied class of PRRs is the Toll-like receptor (TLR) family, which consists of 13 transmembrane glycoprote...

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“…IFN-␥ can up-regulate MMPs and is increased in AAA, implicating it in AAA pathogenesis (4,21,23,24). To examine the role of IFN-␥ in AAA development, IFN-␥-deficient (IFN-␥ Ϫ/Ϫ ) mice underwent CaCl 2 aneurysm induction.…”

Section: Ifn-␥ Deficiency Prevents Aneurysm Formation and Mmp Up-regumentioning

confidence: 99%

Key Roles of CD4+ T Cells and IFN-γ in the Development of Abdominal Aortic Aneurysms in a Murine Model

Xiong

Zhao

Prall

et al. 2004

The Journal of Immunology

188

187

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Abdominal aortic aneurysm (AAA) is one of a number of diseases associated with a prominent inflammatory cell infiltrate and local destruction of structural matrix macromolecules. This inflammatory infiltrate is predominately composed of T lymphocytes and macrophages. Delineating specific contribution of these inflammatory cells and their cytokines in AAA formation is the key to understanding AAA and other chronic inflammatory disease processes. Our previous studies have demonstrated that macrophages are the major source of matrix metalloproteinase-9, which is required for aneurysmal degeneration in the murine AAA model. However, the role of CD4+ T cells, the most abundant infiltrates in aneurysmal aortic tissue, is uncertain. In the present study, we found that in the absence of CD4+ T cells, mice are resistant to aneurysm induction. Previous studies have shown that IFN-γ levels are increased in AAA. IFN-γ is a main product of T cells. Intraperitoneal IFN-γ was able to partially reconstitute aneurysms in CD4−/− mice. Furthermore, mice with a targeted deletion of IFN-γ have attenuation of MMP expression and inhibition of aneurysm development. Aneurysms in IFN-γ−/− mice can be reconstituted by reinfusion of competent splenocytes from the corresponding wild-type mice. This study demonstrates the pivotal role that T cells and the T cell cytokine, IFN-γ, play in orchestrating matrix remodeling in AAA. This study has important implications for other degenerative diseases associated with matrix destruction.

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Expression of Interleukin (IL)-18 and Functional IL-18 Receptor on Human Vascular Endothelial Cells, Smooth Muscle Cells, and Macrophages

Cited by 464 publications

References 49 publications

Human postmortem brain-derived cerebrovascular smooth muscle cells express all genes of the classical complement pathway: A potential mechanism for vascular damage in cerebral amyloid angiopathy and Alzheimer's disease

Human postmortem brain-derived cerebrovascular smooth muscle cells express all genes of the classical complement pathway: A potential mechanism for vascular damage in cerebral amyloid angiopathy and Alzheimer's disease

Group A Streptococcus Activates Type I Interferon Production and MyD88-dependent Signaling without Involvement of TLR2, TLR4, and TLR9

Key Roles of CD4+ T Cells and IFN-γ in the Development of Abdominal Aortic Aneurysms in a Murine Model

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