Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD

Abstract

The deubiquitinase CYLD acts as a key negative regulator to tightly control overactive inflammation. Most anti-inflammatory strategies have focused on directly targeting the positive regulator, which often results in significant side effects such as suppression of the host defence response. Here, we show that inhibition of phosphodiesterase 4B (PDE4B) markedly enhances upregulation of CYLD expression in response to bacteria, thereby suggesting that PDE4B acts as a negative regulator for CYLD. Interestingly, in Cyld-deficient mice, inhibition of PDE4B no longer suppresses inflammation. Moreover, PDE4B negatively regulates CYLD via specific activation of JNK2 but not JNK1. Importantly, ototopical post-inoculation administration of a PDE4 inhibitor suppresses inflammation in this animal model, thus demonstrating the therapeutic potential of targeting PDE4. These studies 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 upregulate CYLD expression.

MicroRNA miR-126-5p Enhances the Inflammatory Responses of Monocytes to Lipopolysaccharide Stimulation by Suppressing Cylindromatosis in Chronic HIV-1 Infection

“…CYLD acts as a negative regulator for Toll-like receptor 2 signaling via negative cross talk with TNF receptor-associated factor 6 (TRAF6) and TRAF7 in 293T cell lines and other cell types (41)(42)(43)(44). Whether CYLD regulates TLR4 signaling in monocytes remains unclear.…”

“…Recent studies have shown that CYLD directly regulates multiple key signaling cascade pathways, such as the NF-B and the MAPK pathways, and acts as a negative regulator for Toll-like receptor 2 signaling via negative cross talk with TRAF6 and TRAF7 (40,41). The inhibition of phosphodiesterase 4B (PDE4B) markedly enhances CYLD expression in response to bacteria and resulted in suppressed inflammation (44). Moreover, a very recent study by the same group showed that CYLD acts as a negative regulator of bacterium nontypeable Haemophilus influenzae (NTHi)-induced inflammation by suppressing K63-linked ubiquitination of myeloid differentiation factor 88 (MyD88) (42).…”

CYLD: a critical regulator of hypoxia-mediated inflammation in tumors

“…Elucidating the mechanisms linking hypoxia-induced CYLD down-regulation and inflammation, and adaptive changes in GBM tissues during anti-VEGF therapy, may provide insights into GBM pathobiology and development of more effective therapeutic approaches to GBM. Recently, Komatsu et al reported that Rolipram, a selective inhibitor for phosphodiesterase 4B (PDE4B), enhanced up-regulation of CYLD expression [86] . This finding suggests that up-regulating the CYLD expression may also have the potential to be promising therapeutic strategies for tumors as the low CYLD expression level has been reported to have an crucial role in the development of tumors in patients [86] .…”

Receptor Interacting Protein-2 acts as negative regulator for nontypeable Haemophilus influenzae-induced mucin MUC5AC expression

“…Western blot procedures were previously described [2][3][4][12][13][14][15][16][17]. Western blots were performed using whole-cell extracts, separated on 8-10 % SDS-PAGE gels, and transferred to polyvinylidene difluoride we hypothesized that RIP-2 may play a critical role in regulating mucin production [22].…”

“…Total RNA extraction and RT-qPCR were performed as previously described [2][3][4][12][13][14][15][16][17]. The relative quantities of mRNAs were determined by using the comparative Ct method and were normalized by using human cyclophilin for in vitro or mouse glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for in vivo as endogenous controls.…”