RT Journal Article
SR Electronic
T1 Validating SIK as a novel COPD target using four different human systems
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P834
VO 44
IS Suppl 58
A1 Melker Göransson
A1 Ulf Hedström
A1 Barbara Fuchs
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/P834.abstract
AB Recent findings identify salt inducible kinases (SIKs) as a key molecular switch, whose inhibition reprograms murine macrophages to an anti-inflammatory phenotype. The underlying chronic inflammation of the airways, triggered by the inhalation of noxious substances such as tobacco smoke, leads to structural changes and narrowing of the small airways in COPD. This inflammatory state is believed to be driven primarily by macrophages, T-lymphocytes and neutrophils. Polarization of macrophages into a regulatory population, that produces high levels of IL-10 and low levels of pro-inflammatory cytokines like TNFa, may play an important role in the resolution of inflammation and is hypothesized to reduce frequency of COPD exacerbations.We have set up assays in four different human systems ranging from THP-1 cells, monocyte-derived macrophages and alveolar macrophages, to lung explant cultures for validation of this target in a human setting.Our data from both “normal” primary cells/tissue from cancer resections as well as COPD derived primary cells/tissue show that the concept of changing the TNFa/IL10 ratio, and thus the inflammatory state of the lung, by inhibiting SIK is conserved from mice to man. However, the level of expression differs between species and the effect is more modest in a human system.The SIK family consists of 3 members and it is not yet fully clear which of the SIK1-3 proteins is important for polarization of macrophages, but recent evidence suggests SIK2 as being the major target in the mouse system. In parallel with the standard target validation strategies, the effect of mutating strategic phosphorylation sites on SIK1-3 in a human cell line will be assessed using TALEN technology.