Soluble receptors in human disease

Heaney, Mark L.; Golde, David W.

doi:10.1002/jlb.64.2.135

Cited by 155 publications

(139 citation statements)

References 182 publications

(117 reference statements)

Supporting

Mentioning

133

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, the effects of IL-1 and IL-1RII with respect to NO and PGE 2 production are not influenced by exogenous addition of other mediators such as IL-6 (data). Uninduced (control) 4.9 Ϯ 0.9 13.9 Ϯ 3.3 ϩ sIL-1RII (250 pg/ml) 1.7 Ϯ 0.5* 2.2 Ϯ 0.9* ϩ sIL-1RII (125 pg/ml) 1.6 Ϯ 0.2* 4.5 Ϯ 1.3* ϩ sIL-1RII (62.5 pg/ml) 2.7 Ϯ 0.9* 5.8 Ϯ 0.1* ϩ IL-1 (1 ng/ml) 16.2 Ϯ 4.7 136.3 Ϯ 40.8 ϩ IL-1 (1 ng/ml) ϩ sIL-1RII (250 pg/ml) 6.0 Ϯ 0.6** 4.5 Ϯ 0.4** IL-1RII, both as a cell-surface receptor and a soluble protein, has unique IL-1 antagonist properties due to its ability to be a functional decoy receptor, thereby making it a promising candidate for pharmacological intervention and gene therapy (42). In order to understand the biology of IL-1RII in inflammatory responses, we stably transfected IL-1RII cDNA in a human chondrocyte cell line (C-20/A4) for expression of this receptor.…”

Section: Discussionmentioning

confidence: 99%

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

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)...

show abstract

Section: Discussionmentioning

confidence: 99%

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

show abstract

“…The receptors for TNF, IL-1, IL-2, macrophage-colony-stimulating factor (M-CSF), platelet-derived growth factor (PDGF), and nerve growth factor (NGF) appear to be subject to proteolytic cleavage, resulting in the shedding of the extracellular part of the respective molecules. 13,14 On the other hand, alternative splicing of the receptor mRNAs resulting in proteins lacking a transmembrane domain have been described for several cell surface molecules, including the receptors for GM-CSF, G-CSF, IL-4, IL-5, IL-7, IL-9, EGF, LIF, erythropoietin, and thrombopoietin. 13,14 However, as analyzed in detail for the sIL-4R of the mouse, 23 for one soluble receptor both mechanisms can occur in the same cell but appear to be activated by distinct pathways.…”

Section: Discussionmentioning

confidence: 99%

“…13,14 On the other hand, alternative splicing of the receptor mRNAs resulting in proteins lacking a transmembrane domain have been described for several cell surface molecules, including the receptors for GM-CSF, G-CSF, IL-4, IL-5, IL-7, IL-9, EGF, LIF, erythropoietin, and thrombopoietin. 13,14 However, as analyzed in detail for the sIL-4R of the mouse, 23 for one soluble receptor both mechanisms can occur in the same cell but appear to be activated by distinct pathways. Several considerations and observations make shedding the most likely mechanism responsible for s␥c production.…”

Section: Discussionmentioning

confidence: 99%

“…Interference with the binding of cytokines to their membrane receptors and, thus, inhibition of cytokine signaling has been demonstrated to occur in vitro and in vivo. 13,14,29 On the other hand, several soluble cytokine receptors have been shown to intensify the activity of their respective cytokines in vivo-eg, by acting as carrier moleculesand to protect the cytokine against proteolytic cleavage 30 or by forming agonistic complexes with their ligands able to interact with other signal-transducing molecules on cells. 31,32 No reports concerning a murine soluble ␥c (s␥c) have been published so far.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, as previously shown for other soluble cytokine receptors, the s␥c represents a molecule with a C-terminus located in proximity to the transmembrane domain of the cell surface anchored receptor. 13,14 To investigate the regulation of s␥c expression, we developed an ELISA-based assay. The specificity of this assay was convincingly demonstrated by the fact that s␥c was undetectable in sera and in cell culture supernatants of ␥c Ϫ/Ϫ mice.…”

mentioning

confidence: 99%

See 2 more Smart Citations

A soluble form of the murine common γ chain is present at high concentrations in vivo and suppresses cytokine signaling

Meißner

Blum

Schnare

et al. 2001

Blood

View full text Add to dashboard Cite

The common gamma-chain (␥c) is a component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 and is essential for their signal transduction. Western blotting and a newly established enzyme-linked immunosorbent assay detected substantial constitutive levels (50-250 ng/mL) of soluble ␥c (s␥c) in sera of murine inbred strains. It was demonstrated that purified immune cells, such as T, B, and natural killer cells, and macrophages released this protein after activation. Transfection experiments with cDNA encoding the fulllength ␥c showed that shedding of the transmembrane receptor led to the release of s␥c. The shedding enzymes, however, appeared to be distinct from those cleaving other cytokine receptors because inhibitors of metalloproteases (eg, TAPI) did not influence s␥c release. In vivo, superantigen-induced stimulation of T cells enhanced s␥c serum concentrations up to 10-fold within 6 hours. Because these findings demonstrated regulated expression of a yet unknown molecule in the immune response, further experiments were performed to assess the possible function(s) of s␥c. A physiological role of s␥c was indicated by its capacity to specifically inhibit cell growth induced by ␥c-dependent cytokines. Mutational analysis revealed that the Cterminus and the WSKWS motif are essential for the cytokine inhibitory effect of the s␥c and for binding of the molecule to cytokine receptor-expressing cells. Thus, competitive displacement of the transmembrane ␥c by excess s␥c is the most likely mechanism of cell growth inhibition. It was implied that naturally produced s␥c is a negative modulator of ␥c-dependent cytokines. IntroductionThe murine common gamma-chain (␥c) is a 64-kd type 1 transmembrane protein of the cytokine receptor family. 1 Although the ␥c alone is unable to bind to cytokines, it has been shown to be an essential component of the cell surface receptor complexes of IL-2, IL-4, IL-7, IL-9, and IL-15. 1 Interaction of the respective cytokines with the ␥c within the receptor complexes results in the activation of the Janus kinase JAK3, 2 which subsequently interacts with Pyk2, a member of focal adhesion tyrosine kinases, leading to the phosphorylation of this protein. 3 Recent studies have shown that the ␥c is critical for lymphoid development because genetic defects of either this molecule 4 or JAK3 5 in humans or targeted deletions of the ␥c 6,7 or JAK3 8-10 in mice severely impair the development of T and B cells, leading to severe combined immune deficiency syndromes (SCID). 11 Soluble cytokine receptors and growth factor receptors are present as immunomodulatory molecules in body fluids of humans and mice (reviewed in references 12 and 14). Two major nonexclusive mechanisms are responsible for the generation of soluble cytokine receptors: proteolytic cleavage of transmembrane receptors catalyzed mostly by metalloproteases [15][16][17][18][19] or de novo synthesis of alternatively spliced mRNAs encoding soluble receptor molecules lacking a transmembrane domain. [20][21][22][23][24][25][26][27][28] ...

show abstract

Effect of Mechanical Ventilation on Inflammatory Mediators in Patients With Acute Respiratory Distress Syndrome

Ranieri¹,

Suter²,

Tortorella³

et al. 1999

JAMA

1,622

326

View full text Add to dashboard Cite

show abstract

Soluble receptors in human disease

Cited by 155 publications

References 182 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

A soluble form of the murine common γ chain is present at high concentrations in vivo and suppresses cytokine signaling

Effect of Mechanical Ventilation on Inflammatory Mediators in Patients With Acute Respiratory Distress Syndrome

Contact Info

Product

Resources

About