Myosin light chain kinase (MLCK; gene code, MYLK) is a
multifunctional enzyme involved in
isoform-specific nonmuscle (nm) and smooth muscle contraction,
inflammation, and vascular permeability, processes directly relevant to
asthma pathobiology. In this report, we highlight the contribution of the nm
isoform (nmMLCK) to
asthma susceptibility and severity, supported by studies in two lines of transgenic mice with knocking out nmMLCK or selectively overexpressing nmMLCK in endothelium. These mice were sensitized to exhibit
ovalbumin-mediated allergic
inflammation. Genetically engineered mice with targeted nmMLCK deletion (nmMLCK(-/-)) exhibited significant reductions in
lung inflammation and
airway hyperresponsiveness. Conversely, mice with overexpressed nmMLCK in endothelium (nmMLCK(ec/ec)) exhibited elevated susceptibility and severity in asthmatic
inflammation. In addition, reduction of nmMLCK expression in pulmonary endothelium by
small interfering RNA results in reduced asthmatic
inflammation in wild-type mice. These pathophysiological assessments demonstrate the positive contribution of nmMLCK to asthmatic
inflammation, and a clear correlation of the level of nmMLCK with the degree of experimental allergic
inflammation. This study confirms MYLK as an
asthma candidate gene, and verifies nmMLCK as a novel molecular target in asthmatic pathobiology.