Molecular subtypes of lung adenocarcinoma present distinct immune tumor microenvironments.

Overcoming resistance to immune checkpoint inhibitors is an important issue in patients with non-small-cell lung cancer (NSCLC). Transcriptome analysis shows that adenocarcinoma can be divided into three molecular subtypes: terminal respiratory unit (TRU), proximal proliferative (PP), and proximal inflammatory (PI), and squamous cell carcinoma (LUSQ) into four. However, the immunological characteristics of these subtypes are not fully understood. In this study, we investigated the immune landscape of NSCLC tissues in molecular subtypes using a multi-omics dataset, including tumor-infiltrating leukocytes (TILs) analyzed using flow cytometry, RNA sequences, whole exome sequences, metabolomic analysis, and clinicopathologic findings. In the PI subtype, the number of TILs increased and the immune response in the tumor microenvironment (TME) was activated, as indicated by high levels of tertiary lymphoid structures, and high cytotoxic marker levels. Patient prognosis was worse in the PP subtype than in other adenocarcinoma subtypes. Glucose transporter 1 (GLUT1) expression levels were upregulated and lactate accumulated in the TME of the PP subtype. This could lead to the formation of an immunosuppressive TME, including the inactivation of antigen-presenting cells. The TRU subtype had low biological malignancy and "cold" tumor-immune phenotypes. Squamous cell carcinoma (LUSQ) did not show distinct immunological characteristics in its respective subtypes. Elucidation of the immune characteristics of molecular subtypes could lead to the development of personalized immune therapy for lung cancer. Immune checkpoint inhibitors could be an effective treatment for the PI subtype. Glycolysis is a potential target for converting an immunosuppressive TME into an antitumorigenic TME in the PP subtype.

Difference in morphology and interactome profiles between orthotopic and subcutaneous gastric cancer xenograft models.

In xenograft models, orthotopic (ORT) engraftment is thought to provide a different tumor microenvironment compared with subcutaneous (SC) engraftment. We attempted to characterize the biological difference between OE19 (adenocarcinoma of the gastroesophageal junction) SC and ORT models by pathological analysis and CASTIN (CAncer-STromal INteractome) analysis, which is a novel method developed to analyze the tumor-stroma interactome framework. In SC models, SCID mice were inoculated subcutaneously with OE19 cells, and tumor tissues were sampled at 3 weeks. In ORT models, SCID mice were inoculated under the serosal membrane of the stomach wall, and tumor tissues were sampled at 3 and 6 weeks after engraftment. Results from the two models were then compared. Histopathologically, the SC tumors were well circumscribed from the adjacent tissue, with scant stroma and the formation of large ductal structures. In contrast, the ORT tumors were less circumscribed, with small ductal structures invading into abundant stroma. Then we compared the transcriptome profiles of human tumor cells with the mouse stromal cells of each model by species-specific RNA sequencing. With CASTIN analysis, we successfully identified several interactions that are known to affect the tumor microenvironment as being selectively enhanced in the ORT model. In conclusion, pathological analysis and CASTIN analysis revealed that ORT models of OE19 cells have a more invasive character and enhanced interaction with stromal cells compared with SC models.

[Problems of Home-Visiting Speech-Language-Hearing Therapists in Dysphagia Management].

There are fewer reports by speech-language-hearing therapists than those by physical therapists or occupational therapists for visiting rehabilitation. Therefore, we examined the present situation with emphasis on professional roles of speech-language- hearing therapists working in visiting rehabilitation, patient tendency, and dysphagia rehabilitation. A questionnaire survey and interview survey were conducted on 6 speech-language-hearing therapists working in visiting rehabilitation. In the questionnaire, personal attributes, subject area, details of dysphagia rehabilitation, professional duties, and tendency of patient in charge were collected. In the interview survey, we asked about trends and request status, evaluation and training protocol for patients with dysphagia, activities related to pneumonia prevention, and future directions in the field. Results show that many linguistichearing experts worked with dysphagia patients, indicating that the needs for respiratory rehabilitation and dysphagia rehabilitation are high. In this survey, the environment surrounding visiting speech-language-hearing therapists and patients with dysphagia was clarified.

Lipopolysaccharide Derived from Pantoea agglomerans Directly Promotes the Migration of Human Keratinocytes.

BACKGROUND/AIM: Because the skin is exposed to the external environment, it is important that wound healing processes proceed and terminate rapidly to minimize the risk of infection. A previous case report described the promotion of wound healing by transdermal administration of lipopolysaccharide derived from Pantoea agglomerans (LPSp). However, whether the wound healing-promoting effect of LPSp was due to direct activity on skin cells or indirect effects involving macrophages remained unclear. Therefore, this study investigated the wound healing-promoting effect of LPSp, particularly the promotion of keratinocyte migration. MATERIALS AND METHODS: The migration of HaCaT human keratinocytes over time with and without LPSp was assayed using a cell migration assay kit. Migration was also analyzed using HaCaT cells treated with LPSp and an antibody against Toll-like receptor (TLR) 4, a receptor for LPS. RESULTS: Addition of LPSp significantly enhanced cell migration compared to no LPSp addition. Migration was inhibited by the addition of anti-TLR4 antibody. CONCLUSION: LPSp acts directly on epidermal cells to promote migration and may be one mechanism by which LPSp promotes wound healing.

Tumor-infiltrating Leukocyte Profiling Defines Three Immune Subtypes of NSCLC with Distinct Signaling Pathways and Genetic Alterations.

Resistance to immune checkpoint blockade remains challenging in patients with non-small cell lung cancer (NSCLC). Tumor-infiltrating leukocyte (TIL) quantity, composition, and activation status profoundly influence responsiveness to cancer immunotherapy. This study examined the immune landscape in the NSCLC tumor microenvironment by analyzing TIL profiles of 281 fresh resected NSCLC tissues. Unsupervised clustering based on numbers and percentages of 30 TIL types classified adenocarcinoma (LUAD) and squamous cell carcinoma (LUSQ) into the cold, myeloid cell-dominant, and CD8+ T cell-dominant subtypes. These were significantly correlated with patient prognosis; the myeloid cell subtype had worse outcomes than the others. Integrated genomic and transcriptomic analyses, including RNA sequencing, whole-exome sequencing, T-cell receptor repertoire, and metabolomics of tumor tissue, revealed that immune reaction-related signaling pathways were inactivated, while the glycolysis and K-ras signaling pathways activated in LUAD and LUSQ myeloid cell subtypes. Cases with ALK and ROS1 fusion genes were enriched in the LUAD myeloid subtype, and the frequency of TERT copy-number variations was higher in LUSQ myeloid subtype than in the others. These classifications of NSCLC based on TIL status may be useful for developing personalized immune therapies for NSCLC. Significance: The precise TIL profiling classified NSCLC into novel three immune subtypes that correlates with patient outcome, identifying subtype-specific molecular pathways and genomic alterations that should play important roles in constructing subtype-specific immune tumor microenvironments. These classifications of NSCLC based on TIL status are useful for developing personalized immune therapies for NSCLC.

Long-term efficacy of plasma exchange treatment for refractory Kawasaki disease.

BACKGROUND: The treatment of Kawasaki disease patients who fail to respond to initial i.v. immunoglobulin (IVIG) therapy is controversial. The aim of the present study was to investigate the long-term efficacy of plasma exchange (PE) treatment for refractory Kawasaki disease. METHODS: A total of 125 Kawasaki disease patients refractory to IVIG were treated with PE. Coronary artery lesions (CAL) before PE, in the acute period, and during the late period were examined retrospectively. RESULTS: Residual sequelae requiring medical treatment occurred in six cases in the late period. The outcomes of treatment tended to be better when PE was begun in the early stage. Sequelae remained in 2.8% of patients in whom PE was initiated prior to day 9 after onset, and were present in 15% of patients in whom PE was started on or after day 10. The 105 patients whose coronary arteries were normal before PE had no sequelae (residual sequelae: 0%). Dilatation was present before PE in 14 patients, but remained in only two patients in the late period (residual sequelae, 14.3%). In four of the six patients in whom aneurysms had already formed before PE, the lesions had advanced into giant aneurysms, but in the other two patients they returned to the normal range (residual sequelae, 66.6%). CONCLUSIONS: The outcomes of PE for Kawasaki disease refractory to IVIG are favorable, and the effectiveness of this treatment is excellent, particularly if it is initiated before CAL arise.

Spatiotemporal dynamics of high-wavenumber turbulence in a basic laboratory plasma.

High-spatial resolution observation of high-wavenumber broadband turbulence is achieved by controlling the magnetic field to be relatively low and measuring with a azimuthally arranged multi-channel Langmuir array in a basic laboratory plasma. The observed turbulence consists of narrowband low-frequency fluctuations and broadband high-frequency turbulent fluctuations. The low-frequency fluctuations have a frequency of about 0.7 times the ion cyclotron frequency and a spatial scale of 1/10 of the ion inertial scale. In comparison, high-frequency fluctuations have a higher frequency than the ion cyclotron frequency and spatial scales of 1/10-1/40 of the ion inertial scale. Two-dimensional correlation analysis evaluates the spatial and temporal correlation lengths and reveals that the high-wavenumber broadband fluctuations have turbulent characteristics. The measurements give us further understanding of small scale turbulence in space and fusion plasmas.

Establishment of preanalytical conditions for microRNA profile analysis of clinical plasma samples.

The relationship between the expression of microRNAs (miRNAs) in blood and a variety of diseases has been investigated. MiRNA-based liquid biopsy has attracted much attention, and cancer-specific miRNAs have been reported. However, the results of analyses of the expression of these miRNAs vary among studies. The reproduction of results regarding miRNA expression levels could be difficult if there are differences in the data acquisition process. Previous studies have shown that the anticoagulant type used during plasma preparation and sample storage conditions could contribute to differences in measured miRNA levels. Thus, the impact of these preanalytical conditions on comprehensive miRNA expression profiles was examined. First, the miRNA expression profiles of samples obtained from healthy volunteers were analyzed using next-generation sequencing. Based on an analysis of the library concentration, human genome identification rate, ratio of unique sequences and expression profiles, the optimal preanalytical conditions for obtaining highly reproducible miRNA expression profiles were established. The optimal preanalytical conditions were as follows: ethylenediaminetetraacetic acid (EDTA) as the anticoagulant, whole-blood storage at room temperature within 6 hours, and plasma storage at 4°C or -20°C within 30 days. Next, plasma samples were collected from 60 cancer patients (3 facilities × 20 patients/facility), and miRNA expression profiles were analyzed. There were no significant differences in measurements except in the expression of erythrocyte-derived hsa-miR-451a. However, the variation in hsa-miR-451a levels was smaller among facilities than among individuals. This finding suggests that samples obtained from the same facility could show significantly different degrees of hemolysis across individuals. We found that the standardization of anticoagulant use and storage conditions contributed to reducing the variation in sample quality across facilities. The findings from this study could be useful in developing protocols for collecting samples from multiple facilities for cancer screening tests.

Kawasaki disease with acute myocarditis in an adolescent.

A previously healthy 16-year-old adolescent was admitted to our hospital with fever, sore throat, diarrhoea, strawberry tongue, rashes on lower extremities, and pain in the neck, abdomen and joints. He was initially diagnosed with IgA vasculitis triggered by acute pharyngitis. Despite antibiotic treatment, he gradually developed multiorgan failure and cardiac shock. Cardiac catheterisation did not show any signs of coronary artery disease. Subsequently, he developed serious rhabdomyolysis and peripheral extremity necrosis, suggesting peripheral arteritis. Although blood culture results were negative, he received endotoxin adsorption therapy, but it was ineffective. Hence, we suspected Kawasaki disease (KD). We administered high-dose intravenous immunoglobulin therapy (2 g/kg), which was effective. He gradually recovered without major complications and was given ambulatory discharge 43 days after admission. Early diagnosis and administration of intensive care in adolescents with KD with acute myocarditis are critical but challenging.

Linoleic acid metabolite suppresses skin inflammation and tumor promotion in mice: possible roles of programmed cell death 4 induction.

(+/-)-13-Hydroxy-10-oxo-trans-11-octadecenoic acid (13-HOA) is one of the lipoxygenase metabolites of linoleic acid (LA) from corn germ. Recently, we reported that this metabolite suppressed the expression of lipopolysaccharide-induced proinflammatory genes in murine macrophages by disrupting mitogen-activated protein kinases and Akt pathways. In this study, we investigated the inhibitory effects of 13-HOA on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation in ears and skin, as well as tumor promotion in female ICR mice. Pretreatment with 13-HOA (1600 nmol) inhibited ear edema formation by 95% (P < 0.05) in an inflammation test and reduced tumor incidence and the number of tumors per mouse by 40 and 64% (P < 0.05 each), respectively, in a two-stage skin carcinogenesis model. Histological examinations revealed that it decreased epidermal thickness, the number of infiltrated leukocytes and cell proliferation index. Furthermore, 13-HOA (8-40 muM) suppressed TPA-induced anchorage-independent growth of JB6 mouse epidermal cells by 70-100%, whereas LA was virtually inactive. 13-HOA (40 muM) inhibited TPA-induced activator protein-1 transactivation but not extracellular signal-regulated kinase1/2 activation. Interestingly, 13-HOA (40 muM and 1600 nmol in JB6 cells and mouse skin, respectively) induced expression of programmed cell death 4 (Pdcd4), a novel tumor suppressor protein. To our knowledge, this is the first report of a food factor that is able to induce Pdcd4 expression. Collectively, our results indicate that 13-HOA may be a novel anti-inflammatory and antitumor chemopreventive agent with a unique mode of action.

Effect of temporary changes in light intensity on carbon transport, partitioning and respiratory loss in young tomato seedlings raised under different light intensities.

Tomato plants were grown under light intensities of 36 or 90 W m(-2) [photosynthetically active radiation (PAR)], and then the light intensity was changed to 36, 90 or 180 W m(-2) for 8 h to investigate the effect of temporary changes in light intensity on the carbon budget of photoassimilates from the third leaf using a (14)CO(2) steady-state feeding method. In the plants that were raised under 90 W m(-2), the photosynthetic rate increased when the light intensity was increased to 180 W m(-2), whereas no increase occurred in the plants that were raised under 36 W m(-2). Although the total amount of carbon fixed during the 8-h light period showed a large difference between plants grown at the two initial light intensities, the proportion of carbon exported during the light period did not differ apparently, irrespective of the change in light intensity. However, the amount of carbon exported during the time course was higher in plants that were raised under 90 W m(-2) than those raised under 36 W m(-2), irrespective of the change in light intensity. The partitioning pattern of (14)C-photoassimilates was not changed by the change in light intensity, irrespective of whether the light intensity was increased or not. However, the amount of (14)C-photoassimilates accumulated in each part differed according to the two initial light intensities. The carbon transport from a source leaf was also investigated through a quantitative analysis of carbon balance.

ROS and innate immunity.

Oxygen is converted into reactive oxygen (RO) by radiation, light, the electron transport system in mitochondria, or by other enzymes and is regulated by the action of antioxidative enzymes which convert RO into an inactive state. Reactive oxygen species (ROS) have a biocidal effect on invading bacteria and they can also injure the cells of the host. For this reason, RO is considered as a general cause of aging and contributes to lifestyle-related diseases and cancer. However, for any organism that uses oxygen as an energy source, RO is inevitably produced and has important biological significance. Apart from the direct activity of RO, recent studies have shown that it functions as a second messenger of signal transduction. In this review, the recent findings related to ROS/nitric oxide (NO) and especially of its relationship to innate immunity are summarized.

Utility and safety of LPS-based fermented flour extract as a macrophage activator.

The immune system is part of the homeostasis system. Our research is focused on ways to maintain health, with an emphasis on the role of macrophages. We have hypothesized that tissue macrophages form a systemic network which we believe contributes to the homeostasis system, and have named it the 'macrophage network.' This network creates a dynamic equilibrium situation where macrophages control homeostasis. Our research is based on this macrophage network theory as we believe that the innate immune system provides the foundation for the homeostasis system. As part of our research, we have demonstrated that macrophage activation can provide protection and therapeutic effects for various diseases. Therefore, we have also focused on lipopolysaccharide (LPS). We proved that the LPS of Pantoea agglomerans (which we have named IP-PA1) was useful in preventing various health disorders and in restoring health when administered via the oral or transdermal route. We also developed a 'fermented flour extract', which consists largely of IP-PA1. For LPS to become a valuable commodity, it is very important to provide assurance about safety (when administered orally or transdermally) to build confidence. For this reason, we tested fermented flour extract (in which the major component was IP-PA1) to confirm that it was safe. The results of these safety trials confirmed that oral and transdermal administration of fermented flour extract was very safe. Thus, we believe that fermented flour extract is a new substance that will have applications in health food, cosmetics, animal feeds, fisheries feeds and drugs industries.

The role of toll-like receptor 2 in survival strategies of Mycobacterium tuberculosis in macrophage phagosomes.

Mycobacterium tuberculosis (Mtb), an intracellular pathogen, is phagocytosed by alveolar macrophage but it is not digested; it survives, proliferates and establishes Mtb infections. The long-term survival mechanism of Mtb is not yet clear. The host's immune response to Mtb is mainly mediated by a Toll-like receptor 2 (TLR2) in macrophages. In the early stage of the immune response by macrophage activation through TLR2, the proliferation of Mtb is suppressed and there is a direct bactericidal effect or induction of apoptosis in infected macrophages. This indicates that TLR2 signaling functions as a defense system against Mtb infection. However, TLR2 signaling from Mtb also appears to be part of the Mtb strategy to escape immune responses by macrophages, such as has been observed when there has been a decrease in MHC-II expression or antigen-processing activity. TLR signaling is reported both to be and not be involved in the maturation of phagosomes, indicating the possibility of contrary influences. In this review, we summarize immune responses of macrophages through TLR2 in Mtb infection, its involvement in phagosome maturation and we describe survival strategies of Mtb through TLR2 signaling.

Intracellular localization of CD14 protein in intestinal macrophages.

BACKGROUND: Our research is focused on intestinal macrophages, which are believed to contribute to the maintenance of intestinal homeostasis. In addition, intestinal macrophages are unique in that there is an impairment of expression of tumor necrosis factor (TNF) from lipopolysaccharide (LPS). This characteristic can be attributed to the lack or poor level of expression of toll-like receptor 4 (TLR4) or CD14 on the membrane of intestinal macrophages. We therefore decided to identify where CD14 was localized in intestinal macrophages. MATERIALS AND METHODS: The endoplasmic reticulum and Golgi apparatus were double stained and the intracellular localization in the intestinal macrophages was observed using a confocal laser microscope. RESULTS: CD14 of peritoneal macrophages was expressed both in the endoplasmic reticulum and Golgi apparatus. By contrast, intestinal macrophages expressed very little CD14 on the cellular membrane. CD14 was present in the endoplasmic reticulum of intestinal macrophages, but was rare in the Golgi apparatus. CONCLUSION: The lack of expression of CD14 on the cell membrane of intestinal macrophages may be caused by transport interference from the endoplasmic reticulum to the Golgi apparatus.

Pollen Allergy Suppression Effect by the Oral Administration of Acetic Acid Bacteria (Gluconacetobacter hansenii).

BACKGROUND/AIM: Gluconacetobacter hansenii (G. hansenii) is an acetic acid bacterium of vinegar production. Its anti-allergic effect on mice upon oral administration was examined. MATERIALS AND METHODS: The amount of LPS was measured by the Limulus reaction. Mice were sensitized by peritoneal and intranasal administration of cedar pollen and alum followed by oral administration of 30 or 150 mg/kg of heated G. hansenii cells. Pollen was administered intranasally to evaluate nasal symptoms, and at 8 weeks, IgE and IL-10 levels in blood were measured by ELISA. RESULTS: The amount of LPS in dried bacterial cells was 10.4±3.3 mg/g. In the cedar pollinosis model of mice, a significant reduction was observed in nose scratching of both groups administered with the bacterial cells (30, 150 mg/kg). CONCLUSION: G. hansenii contains LPS, and its oral administration showed an anti-allergic effect by a significant mitigation of the symptoms in a pollen allergy mouse model.

In vivo effects of mutant RHOA on tumor formation in an orthotopic inoculation model.

Ras homolog family member A (RHOA) mutations are driver genes in diffuse­type gastric cancers (DGCs), and we previously revealed that RHOA mutations contribute to cancer cell survival and cell migration through their dominant negative effect on Rho­associated kinase (ROCK) signaling in vitro. However, how RHOA mutations contribute to DGC development in vivo is poorly understood. In the present study, the contribution of RHOA mutations to tumor morphology was investigated using an orthotopic xenograft model using the gastric cancer cell line MKN74, in which wild­type (WT) or mutated (Y42C and Y42S) RHOA had been introduced. When we conducted RNA sequencing to distinguish between the genes expressed in human tumor tissues from those in mouse stroma, the expression profiles of the tumors were clearly divided into a Y42C/Y42S group and a mock/WT group. Through gene set enrichment analysis, it was revealed that inflammation­ and hypoxia­related pathways were enriched in the mock/WT tumors; however, cell metabolism­ and cell cycle­related pathways such as Myc, E2F, oxidative phosphorylation and G2M checkpoint were enriched in the Y42C/Y42S tumors. In addition, the gene set related to ROCK signaling inhibition was enriched in the RHOA­mutated group, which indicated that a series of events are related to ROCK inhibition induced by RHOA mutations. Histopathological analysis revealed that small tumor nests were more frequent in RHOA mutants than in the mock or WT group. In addition, increased blood vessel formation and infiltration of macrophages within the tumor mass were observed in the RHOA mutants. Furthermore, unlike mock/WT, the RHOA­mutated tumor cells had little antitumor host reaction in the invasive front, which is similar to the pattern of mucosal invasion in clinical RHOA­mutated DGC. These transcriptome and pathological analyses revealed that mutated RHOA functionally contributes to the acquisition of DGC features, which will accelerate our understanding of the contribution of RHOA mutations in DGC biology and the development of further therapeutic strategies.

Cloning and characterization of a TNF-like protein of Plecoglossus altivelis (ayu fish).

Ayu TNF cDNA contains an open reading frame of 708bp encoding 235 amino acids. Poly adeniration (A) signal and eight AU-rich sequences were present in 858bp 3' UTR. Southern blot analysis indicated that ayu TNF is single-copy gene. The genomic DNA sequence of ayu TNF, consisting of four exons and three introns, was shown to be conserved well throughout evolution from fish to mammals. The amino acid sequence of ayu TNF was shown to have 32-41% of amino acid identity to other known fish TNF, and about 30% of amino acid identity to mammalian TNFs. A phylogenetic analysis based on the amino acid sequence of TNF indicated that ayu has a distinctive evolutionary path. Also, two residues of cysteine important for the formation of the three-dimensional structure were conserved in ayu TNF. For the functional analysis, ayu TNF was inserted into expression vector pCold/TF, transferred into Chaperone Competent Cells BL21 (pKJE7); this produced soluble mature ayu recombinant TNF. Ayu recombinant TNF was shown to induce respiratory burst activity from ayu kidney. The above results indicate that ayu TNF plays an important role in phylaxis, as it does in mammals.

DGC-specific RHOA mutations maintained cancer cell survival and promoted cell migration via ROCK inactivation.

RHOA missense mutations exist specifically in diffuse type gastric cancers (DGC) and are considered one of the DGC driver genes, but it is not fully understood how RHOA mutations contribute to DGC development. Here we examined how RHOA mutations affect cancer cell survival and cell motility. We revealed that cell survival was maintained by specific mutation sites, namely G17, Y42, and L57. Because these functional mutations suppressed MLC2 phosphorylation and actin stress fiber formation, we realized they act in a dominant-negative fashion against the ROCK pathway. Through the same inactivating mechanism that maintained cell survival, RHOA mutations also increased cell migration activity. Cell survival and migration studies on CLDN18-ARHGAP (CLG) fusions, which are known to be mutually exclusive to RHOA mutations, showed that CLG fusions complemented cell survival under RHOA knockdown condition and also induced cell migration. Site-directed mutagenesis analysis revealed the importance of the GAP domain and indicated that CLG fusions maintained RHOA in the inactive form. Taken together, these findings show that the inactivation of ROCK would be a key step in DGC development, so ROCK activation might provide novel therapeutic opportunities.

Suppression of response to foreign substances by intestinal macrophages.

Macrophages play an important role in the maintenance of homeostasis by changing their function according to the tissue and environment everywhere in the body. We have proposed that intestinal macrophages, which exist in the front line receiving environmental information, have an important function in forming a macrophage network for biophylaxis. In this review, we introduce intestinal macrophages as an example of the highly plastic and flexible cells adaptable to environmental information. Intestinal macrophages are hyporesponsiveness to foreign substances, especially lipopolysaccharide (LPS), and less expression of CD14 and TLR4/MD-2, receptors for LPS. However, those proteins expression was observed in the cytoplasm of intestinal macrophage. We also found that intestinal macrophages treated with IgA could restore in response to LPS. In conclusion, intestinal macrophages possess the plasticity to respond sensitively to change in their environment and are considered to be involved inflammatory bowel disease development.