The chemoattractant activity of rheumatoid synovial fluid for human lymphocytes is due to multiple cytokines

Al-Mughales, Jamil A.; Blyth, Thomas; Hunter, John; Wilkinson, P. C.

doi:10.1046/j.1365-2249.1996.d01-836.x

Cited by 60 publications

(31 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Targeting chemokines with antibodies or binding proteins as well as targeting chemokine receptors has been attempted as a therapeutic strategy (Gong et al, 1997;Ogata et al, 1997;Plater-Zyberk et al, 1997;Barnes et al, 1998;Halloran et al, 1999;Matthys et al, 2001;Podolin et al, 2002;Yang et al, 2002) However, the overwhelming complexity of these signaling molecules (multiple chemokines, chemokine receptors, and redundancy) is a significant hurdle. Polychemokine (Carter, 2002) or combinations of different chemokine (al Mughales et al, 1996) antagonists have been suggested, but there may be chemokines that act as an agonist at one receptor and an antagonist at another (Xanthou et al, 2003). Despite this complexity, these chemokine receptors and ligands represent a tantalizing therapeutic target because of their integral role in the inflammatory process.…”

Section: Discussionmentioning

confidence: 99%

Small Molecule Disruption of G Protein βγ Subunit Signaling Inhibits Neutrophil Chemotaxis and Inflammation

Lehmann¹,

Seneviratne²,

Smrcka³

2007

Mol Pharmacol

216

209

View full text Add to dashboard Cite

G protein ␤␥ subunit-dependent signaling is important for chemoattractant-dependent leukocyte chemotaxis. Selective small molecule targeting of phosphoinositide 3-kinase (PI3-kinase) ␥ catalytic activity is a target of interest for anti-inflammatory pharmaceutical development. In this study, we examined whether small-molecule inhibition of G␤␥-dependent signaling, including G␤␥-dependent activation of PI3-kinase ␥ and Rac1, could inhibit chemoattractant-dependent neutrophil migration in vitro and inflammation in vivo. Small-molecule G␤␥ inhibitors suppressed fMLP-stimulated Rac activation, superoxide production, and PI3-kinase activation in differentiated HL60 cells. These compounds also blocked fMLP-dependent chemotaxis in HL60 cells and primary human neutrophils. Systemic administration inhibited paw edema and neutrophil infiltration in a mouse carrageenan-induced paw edema model. Overall, the data demonstrate that targeting G␤␥-regulation may be an effective anti-inflammation strategy.Chemoattractant-mediated recruitment of leukocytes is responsible for many of the deleterious effects of chronic inflammatory diseases. Many chemoattractants activate G protein-coupled receptors (GPCRs) coupled to the G i family of heterotrimeric G proteins in leukocytes. Heterotrimeric G proteins are composed of G␣, G␤, and G␥ subunits. Ligand binding to receptors catalyzes the exchange of tightly bound GDP for GTP on the G␣ subunit, liberating it from the G␤␥ subunits. Dissociation of the G␣ and G␤␥ subunits can allow each to directly bind to downstream effector proteins (Gilman, 1987;Oldham and Hamm, 2006). The free G␤␥ subunits released from G i heterotrimers upon chemoattractant receptor activation initiate critical signaling pathways to direct chemoattractant-dependent neutrophil functions including chemotaxis and superoxide production (Neptune and Bourne, 1997).Key direct targets of G␤␥ subunit binding and activation in neutrophils are phosphoinositide 3-kinase ␥ (PI3-kinase ␥) (Stephens et al., 1994(Stephens et al., , 1997Stoyanov et al., 1995), Phospholipase C ␤ (PLC␤) , and P-Rex (Welch et al., 2002). PI3-kinase ␥ has been noted to be a central mediator of chemotaxis and plays a pivotal role in leukocyte recruitment to inflamed tissues (Hirsch et al., 2000;Li et al., 2000;Camps et al., 2005). PIP 3 , produced by PI3-kinase ␥ catalytic activity, is critical to the development of cell polarity, which is necessary for chemokine-mediated cell motility and directional sensing . PI3-kinase ␥-deficient neutrophils have impaired responses to various chemoattractants, including diminished chemotaxis (Hirsch et al., 2000;Li et al., 2000) and respiratory burst (Li et al., 2000;Sasaki et al., 2000), in response to GPCR activation. Small-molecule inhibitors of PI3-kinase ␥ catalytic activity have been demonstrated to suppress joint inflammation in mouse models of inflammation (Barber et al., 2005;Camps et al., 2005). Critical to the success of a method that targets PI3-kinase ␥ activity as a therapeutic anti-inflammatory a...

show abstract

Section: Discussionmentioning

confidence: 99%

Small Molecule Disruption of G Protein βγ Subunit Signaling Inhibits Neutrophil Chemotaxis and Inflammation

Lehmann¹,

Seneviratne²,

Smrcka³

2007

Mol Pharmacol

216

209

View full text Add to dashboard Cite

show abstract

“…206 The presence of multiple chemoattractants in synovial fluid, including IL-15, IL-8, MCP-1, and MIP-1␣, suggests some redundancy in the factors responsible for T-cell extravasation into RA synovial membranes. 205,207 Indeed, recent work has also documented a role for IL-17 208,209 and IL-18 210 in the pathophysiology of this disease, highlighting the complexity of the cytokine cascades at work in RA. Subsequent studies also demonstrated that IL-15-activated T cells from RA patients stimulated macrophage cell lines and primary monocytes/macrophages to produce TNF-␣ in vitro.…”

Section: Role Of Il-15 In Autoimmune and Inflammatory Diseasementioning

confidence: 99%

Interleukin 15: biology and relevance to human disease

Fehniger

Caligiuri

2001

Blood

864

810

View full text Add to dashboard Cite

Since the cloning of interleukin (IL)-15 six years ago, there have been numerous studies examining the molecular and cellular biology of this cytokine. IL-15 and IL-2 have similar biologic properties in vitro, consistent with their shared receptor (R) signaling components (IL-2/15R␤␥ c ). However, specificity for IL-15 versus IL-2 is provided by unique private ␣-chain receptors that complete the IL-15R␣␤␥ and IL-2R␣␤␥ heterotrimeric high-affinity receptor complexes and thereby allow differential responsiveness depending on the ligand and highaffinity receptor expressed. Intriguingly, both IL-15 and IL-15R␣ transcripts have a much broader tissue distribution than IL-2/IL-2R␣. Further, multiple complex posttranscriptional regulatory mechanisms tightly control IL-15 expression. Thus, based upon complex regulation, as well as differential patterns of IL-15 and IL-15R␣ expression, it is likely that the critical in vivo functions of this receptor/ligand pair differ from those of IL-2 and IL-2R␣. Studies to date examining the biology of IL-15 have identified several key nonredundant roles, such as IL-15's importance during natural killer (NK) cell, NK-T cell, and intestinal intraepithelial lymphocyte development and function. A role for IL-15 during autoimmune processes such as rheumatoid arthritis and malignancies such as adult T-cell leukemia suggest that dysregulation of IL-15 may result in deleterious effects for the host. This review attempts to present concisely our current understanding of the cellular and molecular biology of IL-15, IL-15's role in human disease, and its potential clinical utility as a therapeutic agent or target. Molecular and cellular biology of interleukin 15 (IL-15)The discovery of IL-15 and its relation to IL-2 IL-15 was identified by 2 independent groups based upon its ability to stimulate proliferation of the IL-2-dependent CTLL-2 T-cell line in the presence of neutralizing anti-IL-2 antibodies. The activity within cell culture supernatants of the simian kidney epithelial cell line CV-1/EBNA was purified, molecularly cloned, and designated IL-15. 1 The activity identified in supernatants of the human T-cell leukemia virus-1 (HTLV-1) cell line, HuT-102, was purified and called 3 Scientists at the Immunex Corporation (Seattle, WA) isolated the 14-to 15-kd protein responsible for the CTLL proliferation within CV-1/ EBNA supernatants using anion-exchange and high-pressure liquid chromatography and sequenced the NH 2 -terminal residues. Degenerate oligonucleotide primers were generated from this partial protein sequence and were used to obtain the full-length simian IL-15 cDNA from a CV-1/EBNA cDNA library. With simian IL-15 cDNA as a probe, the full-length human IL-15 cDNA was cloned from the IMTLH bone marrow stromal cell line. 1 The IL-T protein identified by researchers at the National Institutes of Health within HuT-102 supernatants was later cloned and shown to be a chimera composed of the HTLV-1 long terminal repeat (LTR) and human IL-15. The HTLV-1 LTR was fused in frame immediatel...

show abstract

“…Interleukin-8 (IL-8), MIP-1alpha and MCP-l have been implicated in rheumatoid arthritis (RA), while MIP-1alpha has been detected in synovial arthritis (12,13). Osteoblastic cells cultured from patients with rheumatoid arthritis or osteoarthritis exhibit strong induction of MCP-1, MIP1alpha and IL-8 (14).…”

Section: Expression Of Chemokines By Osteoblastic Cellsmentioning

confidence: 99%

The expression of monocyte chemoattractant protein-1 and other chemokines by osteoblasts

Graves¹

1999

Front Biosci

View full text Add to dashboard Cite

The chemoattractant activity of rheumatoid synovial fluid for human lymphocytes is due to multiple cytokines

Cited by 60 publications

References 23 publications

Small Molecule Disruption of G Protein βγ Subunit Signaling Inhibits Neutrophil Chemotaxis and Inflammation

Small Molecule Disruption of G Protein βγ Subunit Signaling Inhibits Neutrophil Chemotaxis and Inflammation

Interleukin 15: biology and relevance to human disease

The expression of monocyte chemoattractant protein-1 and other chemokines by osteoblasts

Contact Info

Product

Resources

About