Extracellular Regulation of Interleukin (IL)-1 β through Lung Epithelial Cells and Defective IL-1 Type II Receptor Expression

Coulter, Kristin R.; Wewers, Mark D.; Lowe, Melissa P.; Knoell, Daren L.

doi:10.1165/ajrcmb.20.5.3458

Cited by 41 publications

(40 citation statements)

References 43 publications

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“…In vitro studies have suggested that blockade of both IL-1RII and IL-1ra activity enhances cellular responses to IL-1 (40). Our hypothesis is further strengthened by the recent report, which suggests that lung epithelial cells that lack IL-1RII are more susceptible to IL-1 and inflammatory mediators released by them (41).…”

Section: Discussionsupporting

confidence: 67%

See 1 more Smart Citation

Reversal of Autocrine and Paracrine Effects of Interleukin 1 (IL-1) in Human Arthritis by Type II IL-1 Decoy Receptor

Attur¹,

Dave²,

Cipolletta³

et al. 2000

Journal of Biological Chemistry

118

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Interleukin 1 (IL-1), produced by both synovial cells and chondrocytes, plays a pivotal role in the pathogenesis of cartilage destruction in osteoarthritis (OA). We examined the specific expression and function of IL-1 receptor family-related genes in human joint tissues. Gene array analysis of human normal and OA-affected cartilage showed mRNA expression of IL-1 receptor accessory protein (IL-1RAcp) and IL-1 type I receptor (IL-1RI), but not IL-1 antagonist (IL-1ra) and IL-1 type II decoy receptor (IL-1RII). Similarly, human synovial and epithelial cells showed an absence of IL-1RII mRNA. Functional genomic analyses showed that soluble (s) IL-1RII, at picomolar concentrations, but not soluble TNF receptor:Fc, significantly inhibited IL-1␤-induced nitric oxide (NO) and/or prostaglandin E 2 production in chondrocytes, synovial and epithelial cells. In OA-affected cartilage, the IC 50 for inhibition of NO production by sIL-1RII was 2 log orders lower than that for sIL-1RI. Human chondrocytes that overexpressed IL-1RII were resistant to IL-1-induced IL-1␤ mRNA accumulation and inhibition of proteoglycan synthesis. In osteoarthritis, deficient expression by chondrocytes of innate regulators or antagonists of IL-1 such as IL-1ra and IL-1RII (soluble or membrane form) may allow the catabolic effects of IL-1 to proceed unopposed. The sensitivity of IL-1 action to inhibition by sIL-1RII has therapeutic implications that could be directed toward correcting this unfavorable tissue(s) dependent imbalance. Osteoarthritis (OA)1 is considered a non-inflammatory arthritis, characterized by a limited infiltration of neutrophils into the synovial space and, in general, an absence of the classical signs of inflammation. Chondrocytes embedded within articular cartilage that is avascular and aneural reside in a sequestered environment, perhaps more than other cell types, whereby cellular metabolism is regulated by an autocrine mechanism responsive to biomechanical and pericellular signals. Recent observations by this and other laboratories indicate that, despite the general absence of clinical signs of inflammation, chondrocytes derived from patients with OA, show superinduction of proinflammatory genes typically associated with the products of synovial tissues in rheumatoid arthritis, including nitric-oxide synthase, cyclooxygenase-2, TNF␣, IL-6, and IL-8. The spontaneous production of the corresponding gene products and inflammatory mediators promotes a catabolic state, which leads to progressive cartilage damage in OA (1-4). This intraarticular inflammatory response in OA-affected cartilage, which may be considered as an in situ "molecular inflammation," is partially dependent on autocrine IL-1␤ production, which induces and sustains an imbalance of cartilage homeostasis and extracellular matrix synthesis (5). The autocrine production of IL-1 in OA-affected cartilage is amplified by engagement of integrins such as ␣ 5 ␤ 1 by abnormally expressed extracellular matrix proteins, including proteolytic fragments of fibronectin (5, 6)...

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Section: Discussionsupporting

confidence: 67%

“…Similarly, epithelial cells have been known to lack IL-1RII expression (41). Our experiments show that IL-1RII attenuates the effects of IL-1 in various cell types including rabbit and mouse synovial cells and human epithelial cells.…”

Section: Discussionmentioning

confidence: 53%

Reversal of Autocrine and Paracrine Effects of Interleukin 1 (IL-1) in Human Arthritis by Type II IL-1 Decoy Receptor

Attur¹,

Dave²,

Cipolletta³

et al. 2000

Journal of Biological Chemistry

118

View full text Add to dashboard Cite

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“…3C). This modest increase of NGAL is probably due to a higher basal activity of NGAL and/or a weaker response to IL-1␤ by NHBE cells (15). A slightly larger effect of IL-1␤ stimulation was observed in NHEK cells in which a 5-to 6-fold increase in NGAL was measured in the medium of cells induced for 48 h with IL-1␤ (20 ng/ml) relative to that from unstimulated cells and cells induced by TNF-␣ (20 ng/ml) at the same time points (Fig.…”

Section: Ngal Synthesis Is Up-regulated By Il-1␤mentioning

confidence: 99%

Neutrophil Gelatinase-Associated Lipocalin Is Up-Regulated in Human Epithelial Cells by IL-1β, but Not by TNF-α

Cowland

Sørensen

Sehested

et al. 2003

The Journal of Immunology

323

303

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Synthesis of the antimicrobial protein neutrophil gelatinase-associated lipocalin (NGAL) increases dramatically in bronchial epithelial cells and alveolear type II pneumocytes during lung inflammation. IL-1β induces a >10-fold up-regulation of NGAL expression in the type II pneumocyte-derived cell line A549 cells, whereas TNF-α, IL-6, and LPS had no effect. Similar IL-1β selectivity was demonstrated in primary bronchial epithelial cells and epidermal keratinocytes and for an NGAL promoter fragment transfected into A549 cells. By deletion and substitution analysis of the NGAL promoter, a 40-bp region containing an NF-κB consensus site was found to control the IL-1β-specific up-regulation. Involvement of the NF-κB site was demonstrated by site-directed mutagenesis, by transfection with a dominant-negative inhibitor of the NF-κB pathway, and by EMSA. TNF-α activation of NF-κB, in contrast, did not increase NGAL synthesis, even though induced binding of NF-κB to the NGAL promoter was observed in vitro. IL-1β specificity was not contained within the NF-κB site of the NGAL promoter, as determined by exchanging the NGAL promoter′s NF-κB-binding sequence with that of the IL-8 promoter or with the NF-κB consensus sequence and by testing the NF-κB-binding sequence of the NGAL promoter against the heterologous SV40 promoter. Selectivity for the IL-1 pathway was substantiated by demonstrating that NGAL promoter activity could be induced by LPS stimulation of A549 cells transiently expressing Toll-like receptor 4, which use the same intracellular signaling pathway as the IL-1R. Together, this demonstrates a selective up-regulation of NGAL by the IL-1 pathway.

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“…Previous studies have shown that IL-1␤ induces the production of IL-6 and IL-8 in A549 cells (14). We also compared the sensitivity of IL-1RII ϩ A549 epithelial cells to that of nontransduced cells with respect to the production of IL-6 and IL-8.…”

Section: Regulation Of Il-6 and Il-8 Production By Human Il-1rii ϩ Humentioning

confidence: 98%

“…We have recently shown, using gene expression arrays, that human cartilage and epithelial cells lack the expression of endogenous IL-1␤-antagonizing molecules such as IL-1RII and IL-1Ra (6,14). Both cell types play a profound role in the inflammation and pathophysiology of arthritis, thus making the cartilage and joints susceptible to low concentrations of endogenous IL-1␤.…”

Section: Lack Of Expression Of Il-1rii In Human Chondrocytes and Epitmentioning

confidence: 99%

Functional Genomic Analysis of Type II IL-1β Decoy Receptor: Potential for Gene Therapy in Human Arthritis and Inflammation

Attur

Dave

Leung

et al. 2002

The Journal of Immunology

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Gene expression arrays show that human epithelial cells and human arthritis-affected cartilage lack detectable amounts of mRNA for IL-1 antagonizing molecules: IL-1Ra and IL-1RII, but constitutively express IL-1. Functional genomic analysis was performed by reconstituting human IL-1RII expression in various IL-1RII-deficient cell types to examine its antagonist role using gene therapy approaches. Adenovirus-expressing IL-1RII when transduced into human and bovine chondrocytes, human and rabbit synovial cells, human epithelial cells, and rodent fibroblasts expressed membrane IL-1RII and spontaneously released functional soluble IL-1RII. The IL-1RII+ (but not IL-1RII−) cells were resistant to IL-1β-induced, NO, PGE2, IL-6, and IL-8 production or decreased proteoglycan synthesis. IL-1RII inhibited the function of IL-1 in chondrocytes and IL-1- and TNF-α-induced inflammatory mediators in human synovial and epithelial cells. IL-1RII+ chondrocytes were more resistant to induction of NO and PGE2 by IL-1β compared with IL-1RII− cells incubated with a 10-fold (weight) excess of soluble type II IL-1R (sIL-1RII) protein. In cocultures, IL-1RII+ synovial cells released sIL-1RII, which in a paracrine fashion protected chondrocytes from the effects of IL-1β. Furthermore, IL-1RII+ (but not IL-1RII−) chondrocytes when transplanted onto human osteoarthritis-affected cartilage in vitro, which showed spontaneous release of sIL-1RII for 20 days, inhibited the spontaneous production of NO and PGE2 in cartilage in ex vivo. In summary, reconstitution of IL-1RII in IL-1RII− cells using gene therapy approaches significantly protects cells against the autocrine and paracrine effects of IL-1 at the signaling and transcriptional levels.

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Extracellular Regulation of Interleukin (IL)-1 β through Lung Epithelial Cells and Defective IL-1 Type II Receptor Expression

Cited by 41 publications

References 43 publications

Reversal of Autocrine and Paracrine Effects of Interleukin 1 (IL-1) in Human Arthritis by Type II IL-1 Decoy Receptor

Reversal of Autocrine and Paracrine Effects of Interleukin 1 (IL-1) in Human Arthritis by Type II IL-1 Decoy Receptor

Neutrophil Gelatinase-Associated Lipocalin Is Up-Regulated in Human Epithelial Cells by IL-1β, but Not by TNF-α

Functional Genomic Analysis of Type II IL-1β Decoy Receptor: Potential for Gene Therapy in Human Arthritis and Inflammation

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