Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has become increasingly clear that hyaluronan is more than the simple matrix molecule it was once thought to be but instead takes part in a multitude of biological functions. Three genes encode for hyaluronan synthases (HAS). We demonstrated earlier that HAS2 and HAS3 are constitutively activated in type-B synoviocytes (fibroblast-like synoviocytes) and, furthermore, that the only gene that readily responds to stimulation with a series of proinflammatory cytokines is HAS1. Here we probe the involvement of the transcription factor NF-kappaB in induced and noninduced HAS activation. Transforming growth factor (TGF) beta1 as well as interleukin (IL)-1beta are both strong inducers of HAS1 transcription. Stimulation of fibroblast-like synoviocytes with IL-1beta resulted in rapid degradation of IkappaBalpha, an event that was preceded by IkappaBalpha phosphorylation. Interestingly, TGFbeta1 neither affected IkappaBalpha levels, nor did it cause phosphorylation of IkappaBalpha. In addition, TGFbeta1 had no effect on IkappaBbeta and IkappaBepsilon levels. Electrophorectic mobility shift assays demonstrate that IL-1beta is a potent inducer of NF-kappaB translocation; however, TGFbeta1 treatment did not result in shifting bands. Two adenovirus constructs were used to further clarify differences in TGFbeta1- and IL-1beta-induced HAS1 activation. Overexpressing IkappaBalpha completely abolished the IL-1beta effect on HAS1 but did not interfere with TGFbeta1-induced HAS1 mRNA accumulation. Identical results were obtained when a dominant negative IKK was overexpressed. Interestingly, neither overexpression of IkappaBalpha nor of IKK had any effect on HAS2 and HAS3 mRNA levels. Taken together, HAS1 can be activated by distinct pathways; IL-1beta utilizes NF-kappaB, and TGFbeta1 does not. Furthermore, HAS2 and HAS3 are activated without the involvement of NF-kappaB.
 ...
PMID:Adenovirus-mediated gene transfer of mutated IkappaB kinase and IkappaBalpha reveal NF-kappaB-dependent as well as NF-kappaB-independent pathways of HAS1 activation. 1625 73

One of the hallmarks of arthritis is swollen joints containing unusually high quantities of hyaluronan. Intact hyaluronan molecules facilitate cell migration by acting as ligands for CD44. Hyaluronan degradation products, readily formed at sites of inflammation, also fuel inflammatory processes. Irrespective of whether viruses could be a cause of rheumatoid arthritis, there is clear evidence that links viral infections to this debilitating disease. For this study, live Epstein-Barr virus and a number of double- and single-stranded synthetic viral analogs were tested for their effectiveness as activators of hyaluronan (HA) synthesis. As shown herein, Epstein-Barr virus-treated fibroblast-like synoviocytes significantly increase HA production and release. Real time reverse transcription-PCR data show that HAS1 mRNA levels are significantly elevated in virus-treated cells, whereas mRNA levels for the genes HAS2 and HAS3 remain unchanged. As to the mechanism of virus-induced HAS1 transcription, data are presented that imply that among the double- and single-stranded polynucleotides tested, homopolymeric polycytidylic structures are the most potent inducers of HAS1 transcription and HA release, whereas homopolymeric polyinosinic acid is without effect. Analyses of virus-induced signal cascades, utilizing chemical inhibitors of MAPK and overexpressing mutated IKK and IkappaB, revealed that the MAPK p38 as well as the transcription factor NF-kappaB are essential for virus-induced activation of HAS1. The presented data implicate HAS1 as the culprit in unfettered HA release and point out targets in virus-induced signaling pathways that might allow for specific interventions in cases of unwanted and uncontrolled HA synthesis.
 ...
PMID:Hyaluronan production in synoviocytes as a consequence of viral infections: HAS1 activation by Epstein-Barr virus and synthetic double- and single-stranded viral RNA analogs. 1840 Jul 45

LL-37 is the only human cathelicidin-family host defense peptide and has been reported to interact with invading pathogens causing inflammation at various body sites. Recent studies showed high levels of LL-37 in the synovial-lining membrane of patients with rheumatoid arthritis, a common type of inflammatory arthritis. The present study aims to investigate the role of LL-37 on mechanisms associated with pathogenesis of inflammatory arthritis. The effects of LL-37 on the expression of proinflammatory cytokines, hyaluronan (HA) metabolism-related genes, cell death-related pathways, and cell invasion were investigated in SW982, a human synovial sarcoma cell line. Time-course measurements of proinflammatory cytokines and mediators showed that LL-37 significantly induced IL6 and IL17A mRNA levels at early time points (3-6 hr). HA-metabolism-related genes (i.e., HA synthase 2 (HAS2), HAS3, hyaluronidase 1 (HYAL1), HYAL2, and CD44) were co-expressed in parallel. In combination, LL-37 and IL17A significantly enhanced PTGS2, TNF, and HAS3 gene expression concomitantly with the elevation of their respective products, PGE2, TNF, and HA. Cell invasion rates and FN1 gene expression were also significantly enhanced. However, LL-37 alone or combined with IL17A did not affect cell mortality or cell cycle. Treatment of SW982 cells with both LL-37 and IL17A significantly enhanced IKK and p65 phosphorylation. These findings suggest that the chronic production of a high level of LL-37 may synchronize with its downstream proinflammatory cytokines, especially IL17A, contributing to the co-operative enhancement of pathogenesis mechanisms of inflammatory arthritis, such as high production of proinflammatory cytokines and mediators together with the activation of HA-metabolism-associated genes and cell invasion.
 ...
PMID:LL-37 alone and in combination with IL17A enhances proinflammatory cytokine expression in parallel with hyaluronan metabolism in human synovial sarcoma cell line SW982-A step toward understanding the development of inflammatory arthritis. 3126 Apr 71