Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth.

Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that tumor-associated inflammatory cells may modify lung tumor growth and invasiveness. To determine the role of neutrophil elastase (encoded by Elane) on tumor progression, we used the loxP-Stop-loxP K-ras(G12D) (LSL-K-ras) model of mouse lung adenocarcinoma to generate LSL-K-ras-Elane(-/-) mice. Tumor burden was markedly reduced in LSL-K-ras-Elane(-/-) mice at all time points after induction of mutant K-ras expression. Kaplan-Meier survival analysis showed that whereas all LSL-K-ras-Elane(+/+) mice died, none of the mice lacking neutrophil elastase died. Neutrophil elastase directly induced tumor cell proliferation in both human and mouse lung adenocarcinomas by gaining access to an endosomal compartment within tumor cells, where it degraded insulin receptor substrate-1 (IRS-1). Immunoprecipitation studies showed that, as neutrophil elastase degraded IRS-1, there was increased interaction between phosphatidylinositol 3-kinase (PI3K) and the potent mitogen platelet-derived growth factor receptor (PDGFR), thereby skewing the PI3K axis toward tumor cell proliferation. The inverse relationship identified between neutrophil elastase and IRS-1 in LSL-K-ras mice was also identified in human lung adenocarcinomas, thus translating these findings to human disease. This study identifies IRS-1 as a key regulator of PI3K within malignant cells. Additionally, to our knowledge, this is the first description of a secreted proteinase gaining access to the inside of a cell and altering intracellular signaling.

Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma.

Polymorphisms in the interleukin-4 receptor alpha chain (IL-4R alpha) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4R alpha has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target- and tissue-specific manner to mediate heightened expression of a subset of IL-4- and IL-13-responsive genes involved in allergic inflammation. Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4R alpha-dependent signaling.

Tyrosine Phosphorylation: Biochemical Events Involved in Cyclooxygenase II Activation by IL-1beta

Interleukin-1 induced the expression of cyclooxygenase II in renal mesangial cells. This effect was similar to that seen by phorbol myristate accetate which also induced the message for COX II. Cycloheximide superinduced the message for COX II in the presence of IL-1beta. While the message for COX II when stimulated by PMA was completely inhibited by dexamethasone with concentrations of dexamethasone which inhibited PGE(2) formation, dexamethasone only partially inhibited the message for COX II by Northern analysis. Genistein, an inhibitor of tyrosine phosphorylation completely inhibited the ability of IL-1beta to induce the COX II message. Immunocytochemical studies confirmed the ability of IL-1beta to selectively induce the COX II protein without any effect on COX I protein. These studies confirm the dependency of tyrosine phosphorylation in the IL-1beta induced expression of COX II message and protein.