Apoptosis and inflammation generally exert opposite effects on tumorigenesis: apoptosis serves as a barrier to tumour initiation, whereas inflammation promotes tumorigenesis. Although both events are induced by various common stressors, relatively little is known about the stress-induced signalling pathways regulating these events in tumorigenesis. Here, we show that stress-activated MAP3Ks, ASK1 and ASK2, which are involved in cellular responses to various stressors such as reactive oxygen species, differentially regulate the initiation and promotion of tumorigenesis. ASK2 in cooperation with ASK1 functioned as a tumour suppressor by exerting proapoptotic activity in epithelial cells, which was consistent with the reduction in ASK2 expression in human cancer cells and tissues. In contrast, ASK1-dependent cytokine production in inflammatory cells promoted tumorigenesis. Our findings suggest that ASK1 and ASK2 are critically involved in tumorigenesis by differentially regulating apoptosis and inflammation.

Respiratory epithelial cells play important roles not only in host defense mechanisms, but also in inflammatory responses. Inhaled corticosteroids are widely used for the treatment of patients with inflammatory lung disorders, including asthma, chronic obstructive pulmonary disease, and sarcoidosis. Corticosteroids effectively reduce the production of inflammatory mediators, such as cytokines and chemokines. Although these molecules are also essential for host defense responses, there is no convincing evidence that inhaled corticosteroids increase susceptibility to lower respiratory tract infections. To test the involvement of Toll-like receptor (TLR) family molecules in this phenomenon, we examined the effects of various cytokines and corticosteroid on the expression of TLRs in human respiratory epithelial cells. Among the TLRs tested, TLR2 expression was significantly enhanced after stimulation with a combination of tumor necrosis factor-alpha and interferon-gamma. Dexamethasone synergistically enhanced TLR2 expression in combination with tumor necrosis factor-alpha and interferon-gamma in terms of both mRNA and protein levels. Furthermore, increased cell-surface TLR2 was functional, judging from the remarkable induction of interleukin-6, interleukin-8, and beta-defensin-2 after stimulation with peptidoglycan. These results provide evidence for a novel function of corticosteroids in airway inflammatory disorders, and indicate that the use of inhaled corticosteroids in such disorders may have a beneficial role in host defense mechanisms.

Our study using DNA microarray analysis followed by quantitative real-time polymerase chain reaction reveals over expression of genes related to immune and inflammatory responses, including T-helper type 1 related chemokines, and cytokines such as CXCR3 binding chemokines and TNFSF14. These genes may be potential interstitial cystitis biomarkers.

LPS binding to Toll-like receptor 4 induces a large number of genes through activation of NF-κB and IFN-regulatory factor-3 (IRF-3). However, no previous reports have tested the role of serum proteins in LPS-induced gene expression profiles. To investigate how serum proteins affect LPS-induced signaling, we investigated LPS-inducible genes in PBMC using an oligonucleotide probe-array system. Approximately 120 genes up-regulated by LPS were hierarchically divided into two clusters. Induction of one cluster, containing only IFN-inducible genes, was serum dependent. Real-time PCR analysis confirmed that IFN-inducible genes were induced only in the presence of serum, whereas inflammatory genes were induced both in the presence and absence of serum. Further analysis demonstrated that addition of LPS-binding protein (LBP), but not of soluble CD14 to the serum-free medium enabled the induction of IFN-inducible genes and IFN-β itself by LPS in human monocytes. The mRNAs for IFN-β and IFN-inducible genes were induced by LPS only in the presence of serum from LBP+/+ mice, and not in the presence of serum from LBP−/− mice. Blocking experiments also confirmed the involvement of LBP in this phenomenon. Immunoblotting analysis showed that phosphorylation of c-Jun N-terminal kinase, p38, IRF-3, tyrosine kinase 2, and STAT1 by LPS, but not of NF-κB and extracellular signal-regulated kinase was abrogated in the absence of LBP. This critical role for LBP implies the presence of possible mechanisms linking LBP to the intracellular signaling between Toll-like receptor 4 and IRF-3, leading to the induction of IFN-β by LPS.

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