ABSTRACT
Stat3 mediates a complex spectrum of cellular responses, including inflammation, cell proliferation, and apoptosis. Although evidence exists in support of a positive role for Stat3 in cancer, its role has remained somewhat controversial because of insufficient study of how its genetic deletion may affect carcinogenesis in various tissues. In this study, we show using epithelium-specific knockout mice (Stat3(Δ/Δ)) that Stat3 blunts rather than supports antitumor immunity in carcinogen-induced lung tumorigenesis. Although Stat3(Δ/Δ) mice did not show any lung defects in terms of proliferation, apoptosis, or angiogenesis, they exhibited reduced urethane-induced tumorigenesis and increased antitumor inflammation and natural killer (NK) cell immunity. Comparative microarray analysis revealed an increase in Stat3(Δ/Δ) tumors in proinflammatory chemokine production and a decrease in MHC class I antigen expression associated with NK cell recognition. Consistent with these findings, human non-small cell lung cancer (NSCLC) cells in which Stat3 was silenced displayed an enhancement of proinflammatory chemokine production, reduced expression of MHC class I antigen, and increased susceptibility to NK cell-mediated cytotoxicity. In addition, supernatants from Stat3-silenced NSCLC cells promoted monocyte migration. Collectively, our findings argue that Stat3 exerts an inhibitory effect on antitumor NK cell immunity in the setting of carcinogen-induced tumorigenesis.
Subject(s)
Carcinoma, Non-Small-Cell Lung/immunology , Cell Transformation, Neoplastic , Killer Cells, Natural/immunology , Lung Neoplasms/immunology , STAT3 Transcription Factor/metabolism , Animals , Apoptosis , Carcinogens , Carcinoma, Non-Small-Cell Lung/chemically induced , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Cell Proliferation , Culture Media, Conditioned , Cytokines/biosynthesis , HLA Antigens/biosynthesis , Humans , Lung Neoplasms/chemically induced , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Mice, Knockout , RNA Interference , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Interfering , STAT3 Transcription Factor/genetics , UrethaneABSTRACT
Eosinophils are multifunctional leukocytes typically associated with parasitic helminth infections and allergic diseases, such as bronchial asthma and atopic dermatitis. Although it has been suggested that eosinophils play key roles in various immune functions, including antigen presentation, effector function and immune regulation, the physiological role of eosinophils found early in ontogeny in the thymus and intestine under steady-state conditions remains largely unclear. In this review, we summarize the biological function of eosinophils, focusing on the molecular mechanism underlying their development and trafficking. We also present our recent data that may indicate a novel function of eosinophils in the intestinal lamina propria.
Subject(s)
Eosinophils/physiology , Hypersensitivity/physiopathology , Intestinal Mucosa/physiology , Chemokines/physiology , Humans , Inflammation/physiopathologyABSTRACT
We have developed a novel tuberculosis (TB) vaccine; a combination of the DNA vaccines expressing mycobacterial heat shock protein 65 (HSP65) and interleukin 12 (IL-12) delivered by the hemagglutinating virus of Japan (HVJ)-liposome (HSP65+IL-12/HVJ). This vaccine provided remarkable protective efficacy in mouse and guinea pig models compared to the BCG vaccine, on the basis of an induction of the CTL activity and improvement of the histopathological tuberculosis lesions, respectively. Furthermore, we extended our studies to a cynomolgus monkey model, which is currently the best animal model of human tuberculosis. This novel vaccine provided a higher level of the protective efficacy than BCG based upon the assessment of mortality, the ESR, body weight, chest X-ray findings and immune responses. Furthermore, the combination of HSP65+IL-12/HVJ and BCG by the priming-booster method showed a synergistic effect in the TB-infected cynomolgus monkey (100% survival). These data indicate that our novel DNA vaccine might be useful against Mycobacterium tuberculosis for human clinical trials.
Subject(s)
Bacterial Proteins/immunology , Chaperonins/immunology , Interleukin-12/immunology , Tuberculosis Vaccines/administration & dosage , Tuberculosis/prevention & control , Vaccines, DNA/immunology , Animals , Bacterial Proteins/genetics , Chaperonins/genetics , Disease Models, Animal , Haplorhini , Liposomes/metabolism , Sendai virus , Tuberculosis Vaccines/immunology , Vaccines, Synthetic/immunologyABSTRACT
We have investigated novel vaccine strategies against severe acute respiratory syndrome (SARS) CoV using cDNA constructs encoding the structural antigens: (S), (M), (E), or (N) protein, derived from SARS CoV. PBL from healthy human volunteers were administered i.p. into IL-2 receptor gamma-chain disrupted SCID mice, and SCID-PBL/hu mice were constructed. These mice can be used to analyze the human immune response in vivo. SARS M DNA vaccine and N DNA vaccine induced human CTL specific for SARS CoV antigens. Alternatively, SARS M DNA vaccines inducing human neutralizing antibodies and human monoclonal antibodies against SARS CoV are now being developed. These results show that these vaccines can induce virus-specific immune responses and should provide a useful tool for development of protective and therapeutic vaccines.
