Inhibition of phosphodiesterase 4 modulates cytokine induction from toll like receptor activated, but not rhinovirus infected, primary human airway smooth muscle.
BACKGROUND
Virus-induced exacerbations of Chronic Obstructive Pulmonary Disease (COPD) are a significant health burden and occur even in those receiving the best current therapies. Rhinovirus (RV) infections are responsible for half of all COPD exacerbations. The mechanism by which exacerbations occur remains undefined, however it is likely to be due to virus-induced inflammation. Given that phophodiesterase 4 (PDE4) inhibitors have an anti-inflammatory effect in patients with COPD they present a potential therapy prior to, and during, these exacerbations.


METHODS
In the present study we investigated whether the PDE4 inhibitor piclamilast (10(-6) M) could alter RV or viral mimetic (5 μg/mL of imiquimod or poly I:C) induced inflammation and RV replication in primary human airway smooth muscle cells (ASMC) and bronchial epithelial cells (HBEC). The mediators IL-6, IL-8, prostaglandin E2 and cAMP production were assayed by ELISA and RV replication was assayed by viral titration.


RESULTS
We found that in ASMCs the TLR3 agonist poly I:C induced IL-8 release was reduced while induced IL-6 release by the TLR7/8 agonist imiquimod was further increased by the presence of piclamilast. However, in RV infected ASMCs, virus replication and induced mediator release were unaltered by piclamilast, as was also found in HBECs. The novel findings of this study reveal that although PDE inhibitors may not influence RV-induced cytokine production in ASMCs and replication in either ASMCs or HBECs, they have the capacity to be anti-inflammatory during TLR activation by modulating the induction of these chemotactic cytokines.


CONCLUSIONS
By extrapolating our in vitro findings to exacerbations of COPD in vivo this suggests that PDE4 inhibitors may have beneficial anti-inflammatory properties when patients are infected with bacteria or viruses other than RV.
Woolcock Institute of Medical Research, Sydney, Australia. dvan7422@gmail.com.
David
D
Van Ly
Monique
M
De Pedro
Peter
P
James
Lucy
L
Morgan
Judith L
JL
Black
Janette K
JK
Burgess
Brian G G
BG
Oliver
D000293:Adolescent; D000328:Adult; D000368:Aged; D000634:Aminoquinolines / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001980:Bronchi / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D002478:Cells, Cultured; D015897:Comorbidity; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000187:drug effects* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology; D005260:Female; D006801:Humans; D000077271:Imiquimod; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D010850:Picornaviridae Infections / Q000453:epidemiology / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000453:epidemiology / Q000378:metabolism* / Q000821:virology; D011725:Pyridines / Q000494:pharmacology; D012229:Rhinovirus; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000187:drug effects; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000187:drug effects; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000187:drug effects; D051193:Toll-Like Receptors / Q000187:drug effects / Q000378:metabolism*; D055815:Young Adult
D000634:Aminoquinolines; D001549:Benzamides; D016207:Cytokines; D058988:Phosphodiesterase 4 Inhibitors; D011725:Pyridines; C495344:TLR3 protein, human; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051193:Toll-Like Receptors; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D011070:Poly I-C; D000077271:Imiquimod; C087566:piclamilast