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Researchers Identify Inflammation's Key Negative Regulator

By BiotechDaily International staff writers
Posted on 23 Apr 2013
Researchers working with a genetically engineered mouse model found that blocking the activity of the enzyme PDE4B (phosphodiesterase 4B) suppressed inflammation by increasing the expression of the deubiquitinase enzyme CYLD (cylindromatosis (turban tumor syndrome)).

The PDE4B gene is a member of the type IV, cyclic AMP (cAMP)-specific, cyclic nucleotide phosphodiesterase (PDE) family. Cyclic nucleotides are important second messengers that regulate and mediate a number of cellular responses to extracellular signals, such as hormones, light, and neurotransmitters. The cyclic nucleotide phosphodiesterases (PDEs) regulate the cellular concentrations of cyclic nucleotides and thereby play a role in signal transduction. This gene encodes a protein that specifically hydrolyzes cAMP. Altered activity of this protein has been associated with schizophrenia and bipolar affective disorder.

The ubiquitin-proteasome system is the mechanism by which malfunctioning and possibly toxic proteins are removed from the cell. This system is based on the tagging of damaged proteins with ubiquitin, and the digestion of the subsequent ubiquinated proteins by the proteasome. CYLD is a protease with endodeubiquitinase activity that specifically cleaves lysine-63-linked polyubiquitin chains, thereby removing the ubiquitin tag. This enzyme is a regulator of pathways leading to NF-kappa-B activation and a mediator of cell survival, proliferation, and differentiation via its effects on NF-kappa-B activation. By being a negative regulator of Wnt signaling CYLD promotes acetylation of alpha-tubulin and stabilization of microtubules and is involved in the regulation of microtubule dynamics. Furthermore, CYLD plays a role in the regulation of inflammation and the innate immune response, via its effects on NF-kappa-B activation.

Investigators at Georgia State University (Atlanta, USA) used mice genetically engineered to lack the CYLD gene to determine its role in the process of inflammation.

They reported in the April 9, 2013, online edition of the journal Nature Communications that inhibition of PDE4B markedly enhanced upregulation of CYLD expression in response to bacteria, thereby suggesting that PDE4B acted as a negative regulator for CYLD. In CYLD-deficient mice, inhibition of PDE4B no longer suppressed inflammation. PDE4B negatively regulated CYLD via specific activation of JNK2 (c-Jun N-terminal kinase 2) but not JNK1 (c-Jun N-terminal kinase 1). In addition, postinoculation administration of a PDE4 inhibitor suppressed inflammation in this animal model, thus demonstrating the therapeutic potential of targeting PDE4

The results of this study provide insights into how inflammation is tightly regulated via the inhibition of its negative regulator and may also lead to the development of new anti-inflammatory therapeutics that increase CYLD expression.

"This is the key negative regulator that we have been searching after for years," said senior author Dr. Jian-Dong Li, professor of biology at Georgia State University. "There is a need for better drugs to control inflammation, because current treatments come with serious side effects. Steroids are commonly used, but cannot be used over the long-term, as they suppress the immune system."

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Georgia State University



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