Role of interleukin-6 in antigen-specific mucosal immunoglobulin A induction by cationic liposomes.

The COVID-19 pandemic, caused by a highly virulent and transmissible pathogen, has proven to be devastating to society. Mucosal vaccines that can induce antigen-specific immune responses in both the systemic and mucosal compartments are considered an effective measure to overcome infectious diseases caused by pathogenic microbes. We have recently developed a nasal vaccine system using cationic liposomes composed of 1,2-dioleoyl-3-trimethylammonium-propane and cholesteryl 3ß-N-(dimethylaminoethyl)carbamate in mice. However, the comprehensive molecular mechanism(s), especially the host soluble mediator involved in this process, by which cationic liposomes promote antigen-specific mucosal immune responses, remain to be elucidated. Herein, we show that intranasal administration of cationic liposomes elicited interleukin-6 (IL-6) expression at the site of administration. Additionally, both nasal passages and splenocytes from mice nasally immunized with cationic liposomes plus ovalbumin (OVA) were polarized to produce IL-6 when re-stimulated with OVA in vitro. Furthermore, pretreatment with anti-IL-6R antibody, which blocks the biological activities of IL-6, attenuated the production of OVA-specific nasal immunoglobulin A (IgA) but not OVA-specific serum immunoglobulin G (IgG) responses. In this study, we demonstrated that IL-6, exerted by nasally administered cationic liposomes, plays a crucial role in antigen-specific IgA induction.

Intranasal Immunization with DOTAP Cationic Liposomes Combined with DC-Cholesterol Induces Potent Antigen-Specific Mucosal and Systemic Immune Responses in Mice.

Despite the progress made by modern medicine, infectious diseases remain one of the most important threats to human health. Vaccination against pathogens is one of the primary methods used to prevent and treat infectious diseases that cause illness and death. Vaccines administered by the mucosal route are potentially a promising strategy to combat infectious diseases since mucosal surfaces are a major route of entry for most pathogens. However, this route of vaccination is not widely used in the clinic due to the lack of a safe and effective mucosal adjuvant. Therefore, the development of safe and effective mucosal adjuvants is key to preventing infectious diseases by enabling the use of mucosal vaccines in the clinic. In this study, we show that intranasal administration of a cationic liposome composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 3ß-[N-(N',N'-dimethylaminoethane)-carbamoyl] (DC-chol) (DOTAP/DC-chol liposome) has a potent mucosal adjuvant effect in mice. Intranasal vaccination with ovalbumin (OVA) in combination with DOTAP/DC-chol liposomes induced the production of OVA-specific IgA in nasal tissues and increased serum IgG1 levels, suggesting that the cationic DOTAP/DC-chol liposome leads to the induction of a Th2 immune response. Additionally, nasal-associated lymphoid tissue and splenocytes from mice treated with OVA plus DOTAP/DC-chol liposome showed high levels of IL-4 expression. DOTAP/DC-chol liposomes also enhanced OVA uptake by CD11c+ dendritic cells in nasal-associated lymphoid tissue. These data demonstrate that DOTAP/DC-chol liposomes elicit immune responses via an antigen-specific Th2 reaction. These results suggest that cationic liposomes merit further development as a mucosal adjuvant for vaccination against infectious diseases.

The effect of meloxicam, a selective COX-2 inhibitor, on the microvasculature of small metastatic liver tumors in rats.

BACKGROUND: COX-2 is involved in tumor angiogenesis and modulation of the production of angiogenetic factors by colorectal carcinoma cells. It has been shown that COX-2 inhibitors have inhibitory activities against various types of tumor, including colorectal carcinoma. In this study, we investigated the tumor vessels of small metastatic liver tumors in rats and the effect of meloxicam, a selective COX-2 inhibitor, on their growth and microvasculature. METHODS: The metastatic liver tumors were produced by intraportal inoculation of RCN-H4 cells in male F344/DuCrj rats (n = 40). The microvasculature was examined by scanning electron microscopy and stereomicroscopy. Microvascular casts were produced by perfusion via the abdominal aorta 14 days after tumor inoculation. Four groups (control, groups 1-3) of rats were treated with meloxicam 0, 0.6, 1.0 and 3.0 mg/kg/day, respectively, by oral gavage 5 days/week for two weeks from the day of inoculation of RCN-H4 cells. RESULTS: The mean number of tumors was significantly decreased in groups 1-3 (5.6+/-0.8 standard deviation, SD; 3.6+/-1.1; and 5.5+/-1.1, respectively) compared with control (11.2+/-2.7; P = 0.0002, each). Meloxicam also significantly reduced the mean diameter of the tumor: 730+/-254, 685+/-212 and 644+/-139 in groups 1-3, respectively, in comparison with 870+/-276 in control (P = 0.0025, 0.0011 and <0.0001, respectively). CONCLUSIONS: Meloxicam's anti-angiogenic activity interferes with the growth of metastatic liver tumors. Meloxicam might have therapeutic potential for liver metastasis of colorectal carcinoma.