Functional Diversity and Regulation of Different Interleukin-1 Receptor-Associated Kinase (IRAK) Family Members

Janssens, Sophie; Beyaert, Rudi

doi:10.1016/s1097-2765(03)00053-4

Cited by 518 publications

(416 citation statements)

References 69 publications

Supporting

Mentioning

398

Contrasting

Unclassified

Order By: Relevance

“…Other cell surface markers were tested (CD1a = 4.1%, CD89 = 89%, data not shown). The primary cultures of human fibroblasts were obtained as reported by Janssens et al (22). All reagents used for the cell cultures were endotoxin free, as assayed with the Limulus amebocyte lysate test (Cambrex).…”

Section: Pbmcs Monocyte Isolation and Cell Culturesmentioning

confidence: 99%

Chronic Lymphocytic Leukemia: A Paradigm of Innate Immune Cross-Tolerance

Jurado-Camino

Esteban-Burgos

Hernández-Jiménez

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Infections are a significant cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). The pathogenesis of infections is multifactorial and includes hypogammaglobulinemia, conventional therapy with alkylating drugs, and recently, purine analogs and mAb-associated T cells. Patients without these risk factors also suffer from infections, although the mechanism remains unknown. In a cohort of 70 patients with CLL, we demonstrated that their monocytes were locked into a refractory state and were unable to mount a classic inflammatory response to pathogens. In addition, they exhibited the primary features of endotoxin tolerance, including low cytokine production, high phagocytic activity, and impaired Ag presentation. The involvement of miR-146a in this phenomenon was suspected. We found miR-146a target genes, such as IRAK1 and TRAF6, were manifestly downregulated. Our study provides a new explanation for infections in patients with CLL and describes a cross-tolerance between endotoxins and tumors.

show abstract

Section: Pbmcs Monocyte Isolation and Cell Culturesmentioning

confidence: 99%

Chronic Lymphocytic Leukemia: A Paradigm of Innate Immune Cross-Tolerance

Jurado-Camino

Esteban-Burgos

Hernández-Jiménez

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…It plays a central role in IL-1 and TLR signaling pathways (3,4) and protection from bacterial infections (4). Upon IL-1 stimulation, IRAK4 and IRAK1 colocalize at the IL-1R and both kinases bind to the adaptor protein MyD88.…”

mentioning

confidence: 99%

“…IRAK4 belongs to the IRAK family of kinases, which consists of IRAK1, IRAK2, IRAK-M, and IRAK4 (3). They all contain an N-terminal death domain followed by a linker of unknown domain structure and a kinase domain.…”

mentioning

confidence: 99%

Cutting Edge: IL-1 Receptor-Associated Kinase 4 Structures Reveal Novel Features and Multiple Conformations

Kuglstatter

Villaseñor

Shaw

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

IL-1R-associated kinase (IRAK)4 plays a central role in innate and adaptive immunity, and is a crucial component in IL-1/TLR signaling. We have determined the crystal structures of the apo and ligand-bound forms of human IRAK4 kinase domain. These structures reveal several features that provide opportunities for the design of selective IRAK4 inhibitors. The N-terminal lobe of the IRAK4 kinase domain is structurally distinctive due to a loop insertion after an extended N-terminal helix. The gatekeeper residue is a tyrosine, a unique feature of the IRAK family. The IRAK4 structures also provide insights into the regulation of its activity. In the apo structure, two conformations coexist, differing in the relative orientation of the two kinase lobes and the position of helix C. In the presence of an ATP analog only one conformation is observed, indicating that this is the active conformation.

show abstract

“…IL-1R signalling is initiated by receptor-associated proteins that include TRAFs (TNF receptor-associated factors; Inoue et al, 2000), TIRs (Toll IL-1 receptor proteins; McGettrick and O'Neill, 2004) and IRAKs (IL-1 receptor-associated kinases; Janssens and Beyaert, 2003). IL-1 also activates MAP kinase pathways: p38 (Guan et al, 1997), ERK 1/2 ( (Laporte et al, 1999) and JNK (Guan et al, 1998) and subsequently activates transcription factors such as NF-kb (Roshak et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Inflammation-associated gene expression is altered between normal human ovarian surface epithelial cells and cell lines derived from ovarian adenocarcinomas

et al. 2005

View full text Add to dashboard Cite

Ovulation is believed to contribute to the development of ovarian cancers that derive from the ovarian surface epithelium (OSE). The process of ovulation is synonymous with inflammation and inflammatory cytokines such as interleukin-1a (IL-1a) have recently been shown to induce both inflammatory and anti-inflammatory responses in human OSE (HOSE) cells. In this study we directly compared levels of IL-1a-induced gene expression by analysing the levels of 11b-hydroxysteroid dehydrogenase (11bHSD) types 1 (11bHSD-1) and 2 (11bHSD-2), cyclooxygenase-2 (COX-2), IL-1 receptor (IL-1R) and glucocorticoid receptor a (GRa) mRNA between normal HOSE cells and cell lines derived from poorly differentiated (SKOV-3, BG-1, PEO-4) and well-differentiated (PEO-14) ovarian adenocarcinoma. In HOSE cell cultures, and to a lesser extent PEO-14 cells, the basal mRNA levels of COX-2 and 11bHSD-1 were relatively high and further shown to be induced in response to IL-1a (for HOSE cells; 420-fold, Po0.05 and PEO-14 cells; 43fold, Po0.05). However, whereas HOSE cells expressed a low level of 11bHSD-2 mRNA that was only mildly responsive to IL-1a (1.3-fold, Po0.001), all cell lines exhibited a higher basal level of 11bHSD-2 mRNA that was in some cases further stimulated in PEO-4 cells (five-fold; Po0.05) or suppressed in SKOV-3 cells (two-fold; Po0.01) in response to IL-1a. All cells tested expressed IL-1R and, with the exception of BG-1, GRa. These results indicate that cell lines derived from ovarian cancers have lost the ability to respond normally to inflammatory cytokines such as IL-1a. The finding that normal OSE cells, in contrast to cell lines derived from patients with ovarian adenocarcinoma, abundantly express 11bHSD-1 mRNA but are essentially devoid of 11bHSD-2 mRNA supports the concept that the pattern of 11bHSD isoform gene expression is a defining feature of neoplastic cellular transformation, which might have particular relevance to the ovary.

show abstract

Functional Diversity and Regulation of Different Interleukin-1 Receptor-Associated Kinase (IRAK) Family Members

Cited by 518 publications

References 69 publications

Chronic Lymphocytic Leukemia: A Paradigm of Innate Immune Cross-Tolerance

Chronic Lymphocytic Leukemia: A Paradigm of Innate Immune Cross-Tolerance

Cutting Edge: IL-1 Receptor-Associated Kinase 4 Structures Reveal Novel Features and Multiple Conformations

Inflammation-associated gene expression is altered between normal human ovarian surface epithelial cells and cell lines derived from ovarian adenocarcinomas

Contact Info

Product

Resources

About