Details of a Researcher - Mikami, Yohei

Papers - Mikami, Yohei

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IL-22-producing RORgammat-dependent innate lymphoid cells play a novel protective role in murine acute hepatitis

Matsumoto, A., Kanai, T., Mikami, Y., Chu, P. S., Nakamoto, N., Ebinuma, H., Saito, H., Sato, T., Yagita, H. and Hibi, T.

PLoS One 8 ( 4 ) e62853 2013

ISSN 1932-6203

Retinoid-related orphan receptor (ROR) gammat is known to be related to the development and function of various immunological compartments in the liver, such as Th17 cells, natural killer T (NKT) cells, and innate lymphoid cells (ILCs). We evaluated the roles of RORgammat-expressing cells in mouse acute hepatitis model using RORgammat deficient (RORgammat(-/-)) mice and RAG-2 and RORgammat double deficient (RAG-2(-/-) x RORgammat(-/-)) mice. Acute hepatitis was induced in mice by injection with carbon tetrachloride (CCl4), to investigate the regulation of liver inflammation by RORgammat-expressing cells. We detected RORC expression in three compartments, CD4(+) T cells, NKT cells, and lineage marker-negative SCA-1(+)Thy1(high) ILCs, of the liver of wild type (WT) mice. CCl4-treated RORgammat(-/-) mice developed liver damage in spite of lack of RORgammat-dependent cells, but with reduced infiltration of macrophages compared with WT mice. In this regard, ILCs were significantly decreased in RAG-2(-/-) x RORgammat(-/-) mice that lacked T and NKT cells. Surprisingly, RAG-2(-/-) x RORgammat(-/-) mice developed significantly severer CCl4-induced hepatitis compared with RAG-2(-/-) mice, in accordance with the fact that hepatic ILCs failed to produce IL-22. Lastly, anti-Thy1 monoclonal antibody (mAb), but not anti-NK1.1 mAb or anti-asialo GM1 Ab administration exacerbated liver damage in RAG-2(-/-) mice with the depletion of liver ILCs. Collectively, hepatic RORgammat-dependent ILCs play a part of protective roles in hepatic immune response in mice.

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MyD88-dependent interleukin-10 production from regulatory CD11b(+)Gr-1(high) cells suppresses development of acute cerulein pancreatitis in mice

Koike, Y., Kanai, T., Saeki, K., Nakamura, Y., Nakano, M., Mikami, Y., Yamagishi, Y., Nakamoto, N., Ebinuma, H. and Hibi, T.

Immunol Lett 148 ( 2 ) 172 - 7 2012.12

ISSN 0165-2478

We explored the role of the MyD88 signaling pathway. This pathway mediates the recognition of pathogen-associated molecular patterns and damage-associated molecular patterns via Toll-like receptors (TLRs) and/or IL-1/IL-18 via each cytokine receptor in a murine model of acute pancreatitis induced by cerulein administration. Our analysis revealed that: various TLRs and MyD88 molecules were constitutively expressed in the pancreas of cerulein-treated and untreated wild-type (WT) mice. MyD88(-)/(-) mice administered cerulein developed severe pancreatitis as compared with MyD88(+)/(+) WT mice. The number of IL-10-expressing CD11b(+)Gr-1(high) cells in cerulein-administered MyD88(-)/(-) mice was significantly decreased. This was in accordance with a reciprocal increase in the infiltration of CD4(+) T cells as compared with that in control MyD88(+)/(+) mice. WT mice pretreated with antibiotics and administered cerulein developed milder pancreatitis as compared with control cerulein-administered mice without antibiotic treatment. The MyD88 signaling pathway contributes to the induction of regulatory IL-10-producing macrophages/myeloid-derived suppressor cells, possibly in response to non-bacterial components in the damaged pancreas. These results provide a new concept for therapeutic strategies against acute pancreatitis.

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Anticoagulation therapy dramatically improved severe sigmoiditis with findings resembling inflammatory bowel disease, which was caused by mesenteric venous thrombosis

Mikami, Y., Kanai, T., Iwasaki, E., Naganuma, M., Yamagishi, Y., Shimoda, M., Matsuoka, K., Hisamatsu, T., Iwao, Y., Ogata, H., Nakatsuka, S., Mukai, M. and Hibi, T.

Clin J Gastroenterol 5 ( 6 ) 377 - 82 2012.12

ISSN 1865-7257

Mesenteric venous thrombosis is an insidious disease, with a high mortality rate typically attributed to the long delay in diagnosis. Rapid diagnosis and treatment are important. Here, we present a patient with idiopathic inferior mesenteric venous (IMV) thrombosis. A 65-year-old man presented with constant abdominal pain associated with fever and bloody diarrhea. He was diagnosed with severe ulcerative colitis and was treated with mesalazine and prednisolone. The prednisolone was tapered because of liver dysfunction, and he received total parenteral nutrition for a month. His abdominal pain and bloody diarrhea worsened, and he lost 5 kg of weight. He was then transferred to our institute. Computed tomography showed thickening of the left colon. Colonoscopy showed diffuse colitis with multiple ulcers, large edematous folds, congested mucosa, and stenosis of the sigmoid colon, with sparing of the rectum, raising the possibility of IMV thrombosis. Angiography confirmed IMV thrombosis. Anticoagulation therapy was initiated with intravenous heparin followed by oral warfarin. His abdominal pain and diarrhea resolved, and he was discharged from hospital. Six months later, he remained asymptomatic with normal colonoscopic findings.

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Dysregulated balance of retinoid-related orphan receptor gammat-dependent innate lymphoid cells is involved in the pathogenesis of chronic DSS-induced colitis

Kimura, K., Kanai, T., Hayashi, A., Mikami, Y., Sujino, T., Mizuno, S., Handa, T., Matsuoka, K., Hisamatsu, T., Sato, T. and Hibi, T.

Biochem Biophys Res Commun 427 ( 4 ) 694 - 700 2012.11

ISSN 0006-291X

Retinoid-related orphan receptor (ROR) gammat-expressing and IL-22-producing NKp46(+) innate lymphoid (ILC22) cells reside in the lamina propria of the intestine in mice, suggesting that ILC22 cells contribute to host defense during intestinal damage in models of colitis in mice. Nevertheless, another set of pathological interferon (IFN)-gamma and/or IL-17A-producing innate lymphoid cells (ILC1 and ICL17) may participate in the pathogenesis in different models of colitis. We here showed that RORgammat(+)IL-22(+) ILC22 cells were localized in Thy-1(high)SCA-1(high) and/or Thy-1(high)SCA-1(low) subpopulations of the intestine in normal and dextran sodium sulfate (DSS)-induced colitic RORgammat-sufficient Rag-2(-/-) mice. RORgammat-deficient Rag-2(-/-) mice developed more severe DSS-induced colitis accompanied with lower expression of REG3beta and REG3gamma in the colon, but with a lower ratio and absolute number of IFN-gamma-producing ILC1 cells as compared to control RORgammat-sufficient Rag-2(-/-) mice. Collectively, not only the presence of ILC22 cells but also the balance of protective and pathogenic ILCs may be involved in the prevention of colitis.

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T-helper 17 and interleukin-17-producing lymphoid tissue inducer-like cells make different contributions to colitis in mice

Ono, Y., Kanai, T., Sujino, T., Nemoto, Y., Kanai, Y., Mikami, Y., Hayashi, A., Matsumoto, A., Takaishi, H., Ogata, H., Matsuoka, K., Hisamatsu, T., Watanabe, M. and Hibi, T.

Gastroenterology 143 ( 5 ) 1288 - 1297 2012.11

ISSN 0016-5085

BACKGROUND & AIMS: T helper (Th) 17 cells that express the retinoid-related orphan receptor (ROR) gammat contribute to the development of colitis in mice, yet are found in normal and inflamed intestine. We investigated their development and functions in intestines of mice. METHODS: We analyzed intestinal Th17 cells in healthy and inflamed intestinal tissues of mice. We analyzed expression of lymphotoxin (LT)alpha by Th17 cells and lymphoid tissue inducer-like cells. RESULTS: LTalpha(-/-) and RORgammat(-/-) mice had significantly lower percentages of naturally occurring Th17 cells in the small intestine than wild-type mice. Numbers of CD3(-)CD4(+/-)interleukin-7Ralpha(+)c-kit(+)CCR6(+)NKp46(-) lymphoid tissue inducer-like cells that produce interleukin-17A were increased in LTalpha(-/-) and LTalpha(-/-) x recombination activating gene (RAG)-2(-/-) mice, compared with wild-type mice, but were absent from RORgammat(-/-) mice. Parabiosis of wild-type and LTalpha(-/-) mice and bone marrow transplant experiments revealed that LTalpha-dependent gut-associated lymphoid tissue structures are required for generation of naturally occurring Th17 cells. However, when wild-type or LTalpha(-/-) CD4(+)CD45RB(high) T cells were transferred to RAG-2(-/-) or LTalpha(-/-)xRAG-2(-/-) mice, all groups, irrespective of the presence or absence of LTalpha on the donor or recipient cells, developed colitis and generated Th1, Th17, and Th17/Th1 cells. RAG-2(-/-) mice that received a second round of transplantation, with colitogenic but not naturally occurring Th17 cells, developed intestinal inflammation. The presence of naturally occurring Th17 cells in the colons of mice inhibited development of colitis after transfer of CD4(+)CD45RB(high) T cells and increased the numbers of Foxp3(+) cells derived from CD4(+)CD45RB(high) T cells. CONCLUSIONS: Gut-associated lymphoid tissue structures are required to generate naturally occurring Th17 cells that have regulatory activities in normal intestines of mice, but not for colitogenic Th17 and Th17/Th1 cells during inflammation.

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IgA plasma cells express the negative regulatory co-stimulatory molecule programmed cell death 1 ligand and have a potential tolerogenic role in the intestine

Doi, T., Kanai, T., Mikami, Y., Sujino, T., Jun, L., Ono, Y., Hayashi, A. and Hibi, T.

Biochem Biophys Res Commun 425 ( 4 ) 918 - 23 2012.09

ISSN 0006-291X

To maintain immune homeostasis in the intestine, the intestinal immune system has evolved several tolerogenic mechanisms toward intestinal microflora and food antigens. Although programmed cell death-1 (PD-1) protein has been implicated in immunological tolerance in the intestine and gut-associated lymphoid tissues (GALTs), distribution of its ligands PD-L1 and PD-L2 in the small intestine lamina propria (LP) are unknown. We investigated PD-L1 expression in intestinal LP and found that IgA plasma cells (PCs) were major PD-L1 expressing cells. PD-L1 expression levels on IgA PCs were higher than that on IgG PCs in peripheral lymphoid tissues. IgA PCs expressed antigen-presenting molecule MHC class II and co-stimulatory molecules CD80, CD86, and PD-L2. IgA PCs isolated from intestinal LP exhibited antigen presentation activity, and in the presence of TGF-beta induced FoxP3(+) regulatory T cells, but not IFN-gamma(+) Th1 cells, from naive T cells. Thus, IgA PCs in the intestine may be involved in an immune regulatory role in the intestinal immune system.

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CCR9+ macrophages are required for eradication of peritoneal bacterial infections and prevention of polymicrobial sepsis

Mizukami, T., Kanai, T., Mikami, Y., Hayashi, A., Doi, T., Handa, T., Matsumoto, A., Jun, L., Matsuoka, K., Sato, T., Hisamatsu, T. and Hibi, T.

Immunol Lett 147 ( 1-2 ) 75 - 9 2012.09

ISSN 0165-2478

Sepsis is a systemic inflammatory response to infection associated with multiple organ dysfunction syndrome and a high mortality rate. In septic shock induced by severe peritonitis, early response of peritoneal macrophages against infected microbes is vital in preventing the spread of infection. We found that the mucosal homing receptor CCR9, is induced in peritoneal macrophages in response to inflammatory stimulation. We used a cecal ligation and puncture (CLP) model of sepsis to determine the role of CCR9 with respect to peritoneal macrophages, and controlling peritoneal infection and systemic inflammation. CCR9(-/-) mice showed aggravated septic shock with higher mortality rates compared with wild-type (WT) mice. Six hours after CLP, CCR9(-/-) mice demonstrated a greater inflammatory response. This was associated with higher production of inflammatory cytokines, such as IL-6, TNF and IP-10 in peritoneal lavage compared with WT mice. Although the numbers of peritoneal bacteria were elevated in CCR9(-/-) mice subjected to CLP compared with WT mice, this was normalized in CCR9(-/-) mice subjected to CLP through the adoptive transfer of WT peritoneal macrophages. We conclude that CCR9 is required for recruitment of peritoneal macrophages in the steady state to control systemic sepsis during early phases of peritoneal infection.

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CCR9+ plasmacytoid dendritic cells in the small intestine suppress development of intestinal inflammation in mice

Mizuno, S., Kanai, T., Mikami, Y., Sujino, T., Ono, Y., Hayashi, A., Handa, T., Matsumoto, A., Nakamoto, N., Matsuoka, K., Hisamatsu, T., Takaishi, H. and Hibi, T.

Immunol Lett 146 ( 1-2 ) 64 - 9 2012.08

ISSN 0165-2478

Almost all mice lacking specific molecules associated with regulatory T cells or barrier function develop intestinal inflammation in the colon, but not in the small intestine (SI). Therefore, intestinal homeostasis of the SI may be tightly controlled by other mechanisms. To determine the role of CCR9(+) plasmacytoid dendritic cells (pDCs) in intestinal homeostasis of the SI we transferred CD4(+)CD45RB(high) T cells into ccr9(-/-)xrag-2(-/-) mice. We showed that CCL25, a counterpart chemokine for CCR9, is constitutively expressed in the SI but not the colon and spleen of rag-2(-/-) or ccr9(-/-)xrag-2(-/-) mice before or after transfer of CD4(+)CD45RB(high) T cells. The ccr9(-/-)xrag-2(-/-) mice did not develop spontaneous intestinal inflammation in the SI and colon. Mice of both genotype where CD4(+)CD45RB(high) T cells were transferred developed colitis. However, the ccr9(-/-)xrag-2(-/-) mice also developed ileitis with marked infiltration of Th1 cells. These results suggest that CCR9(+) pDCs are possibly small, regulatory, antigen-presenting cells of the intestine that suppress intestinal inflammation.

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RORgammat-dependent IL-17A-producing cells in the pathogenesis of intestinal inflammation

Kanai, T., Mikami, Y., Sujino, T., Hisamatsu, T. and Hibi, T.

Mucosal Immunol 5 ( 3 ) 240 - 7 2012.05

ISSN 1933-0219

The hypothesis of helper T (T(h))1/T(h)2 cytokine balance proposed by Mosmann and Coffman is often invoked to explain the development of inflammatory diseases, including inflammatory bowel diseases (IBD). Recently, however, a newly identified class of T(h) cells-T(h)17 cells, which produce T(h)17 family cytokines-has been recognized as an essential subpopulation in the development of almost all kinds of human and animal inflammatory diseases, rather than T(h)1 and T(h)2 cells. A representative T(h)17 family cytokine, interleukin (IL)-17A, is produced by not only T(h)17 cells, but also by other types of cells, such as T-cell receptor gammadelta T cells, natural killer (NK) T cells, NK cells, myeloid cells, and innate lymphoid cells, which may also be critically involved in the initiation and persistence of IBD. Here we review recent advances in the study of such IL-17A-producing cells in the pathogenesis of IBD.

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CCR9+ macrophages are required for acute liver inflammation in mouse models of hepatitis

Nakamoto, N., Ebinuma, H., Kanai, T., Chu, P. S., Ono, Y., Mikami, Y., Ojiro, K., Lipp, M., Love, P. E., Saito, H. and Hibi, T.

Gastroenterology 142 ( 2 ) 366 - 76 2012.02

ISSN 0016-5085

BACKGROUND & AIMS: Antigen-presenting cells (APCs) are involved in the induction of liver inflammation. We investigated the roles of specific APCs in the pathogenesis of acute liver injury in mice. METHODS: We used concanavalin A (con A) or carbon tetrachloride to induce acute liver inflammation in mice and studied the roles of macrophages that express CCR9. RESULTS: After injection of con A, we detected CCR9(+)CD11b(+)CD11c(-) macrophages that express tumor necrosis factor (TNF)-alpha in livers of mice, whereas CCR9(+)Siglec-H(+)CD11b(-)CD11c(low) plasmacytoid DCs (pDCs), which are abundant in normal livers, disappeared. The CCR9(+) macrophages were also detected in the livers of RAG-2(-/-) mice, which lack lymphocytes and natural killer T cells, after injection of con A. Under inflammatory conditions, CCR9(+) macrophages induced naive CD4(+) T cells to become interferon gamma-producing Th1 cells in vivo and in vitro. CCR9(-/-) mice injected with con A did not develop hepatitis unless they also received CCR9(+) macrophages from mice that received con A; more CCR9(+) macrophages accumulated in their inflamed livers than CCR9(+) pDCs, CCR9(-) pDCs, or CCR9(-) macrophages isolated from mice that had received injections of con A. Levels of CCL25 messenger RNA increased in livers after injection of con A; neutralizing antibodies against CCL25 reduced the induction of hepatitis by con A by blocking the migration of CCR9(+) macrophages and their production of TNF-alpha. Peripheral blood samples from patients with acute hepatitis had greater numbers of TNF-alpha-producing CCR9(+)CD14(+)CD16(high) monocytes than controls. CONCLUSIONS: CCR9(+) macrophages contribute to the induction of acute liver inflammation in mouse models of hepatitis.

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Regulatory T cells suppress development of colitis, blocking differentiation of T-helper 17 into alternative T-helper 1 cells

Sujino, T., Kanai, T., Ono, Y., Mikami, Y., Hayashi, A., Doi, T., Matsuoka, K., Hisamatsu, T., Takaishi, H., Ogata, H., Yoshimura, A., Littman, D. R. and Hibi, T.

Gastroenterology 141 ( 3 ) 1014 - 23 2011.09

ISSN 0016-5085

BACKGROUND & AIMS: Although T-helper (Th) 17 and Th1 cells are involved in pathogenesis of intestinal inflammation, their developmental pathways and sufficiency to promote disease are not known; nor are the roles of CD4(+)CD25(+) regulatory T (T(R)) cells in their development. METHODS: We performed adoptive transfer experiments to investigate the induction and suppression of colitis using naive CD4(+)CD45RB(high) T cells and/or CD4(+)CD25(+) T(R) cells that were obtained from retinoid-related orphan receptor gamma t (RORgammat) gfp/(+) or Ly5.1/Ly5.2 congenic mice. RESULTS: We observed 3 types of colitogenic CD4(+) Th1 cells (interleukin [IL]-17A(-)interferon [IFN]-gamma(+)): RORgammat(-) classical Th1 cells that differentiated directly from naive T cells; RORgammat(+) Th1-like cells; and RORgammat(-) alternative Th1 cells that were terminally differentiated from RORgammat(+) cells via Th17 (IL-17A(+)IFN-gamma(-)), Th17/Th1 (IL-17A(+)IFN-gamma(+)), or Th1-like (IL-17A(-)IFN-gamma(+)) cells. In this pathway, CD4(+)CD25(+) T(R) cells suppress the development of not only classical Th1 cells, but also alternative Th1 cells at the transition of Th17/Th1 into alternative Th1 cells, resulting in accumulation of Th17 and Th17/Th1 cells in mice in which the development of colitis was suppressed. Furthermore, T(R) cells regulated the established balance of Th17 and Th1 cells under colitic conditions to yield a high ratio of Th17 and Th17/Th1 cells to Th1 cells in noncolitic conditions. CONCLUSIONS: Th17 and Th17/Th1 cells become colitogenic alternative Th1 cells via Th17, Th17/Th1, and Th1-like cells, independently of classical Th1 cells. T(R) cells suppress this pathway, resulting in accumulation of Th17 and Th17/Th1 cells.

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MyD88-dependent pathway accelerates the liver damage of Concanavalin A-induced hepatitis

Ojiro, K., Ebinuma, H., Nakamoto, N., Wakabayashi, K., Mikami, Y., Ono, Y., Po-Sung, C., Usui, S., Umeda, R., Takaishi, H., Yamagishi, Y., Saito, H., Kanai, T. and Hibi, T.

Biochem Biophys Res Commun 399 ( 4 ) 744 - 9 2010.09

ISSN 0006-291X

We have explored the pathological role of the MyD88 signaling pathway via Toll-like receptors (TLRs) that mediate the recognition of pathogen-associated molecular patterns (PAMPs) in a murine model of autoimmune hepatitis induced by administering Concanavalin A (ConA). We first found that various TLRs and MyD88 molecules were expressed in liver of Con A-treated and untreated wild-type (WT) mice including liver macrophages. Flowcytometric analysis revealed that liver CD11b(+)CD11c(-) and CD11b(+)CD11c(+) antigen-presenting cells express TLR2, although NK and NKT cells did not. When WT and MyD88(-/-) mice were intravenously administered with Con A, the severity of hepatitis was significantly lower in Con A-injected MyD88(-/-) mice than in WT mice in terms of the histopathology, the levels of serum transaminase and pro-inflammatory cytokines (TNF-alpha, IFN-gamma, and IL-6), and upregulation of CD80/CD86 and TNF-alpha on/in liver macrophages. The results provide evidence of a possible contribution of the TLRs-MyD88 signaling pathway in activating TLR-expressing liver macrophages in the autoimmune hepatitis model, and thus indicate that the strategy of blockade of pathological pathogens via the intestinal lumen may be feasible for the treatment of the disease.

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Competition between colitogenic Th1 and Th17 cells contributes to the amelioration of colitis

Mikami, Y., Kanai, T., Sujino, T., Ono, Y., Hayashi, A., Okazawa, A., Kamada, N., Matsuoka, K., Hisamatsu, T., Okamoto, S., Takaishi, H., Inoue, N., Ogata, H. and Hibi, T.

Eur J Immunol 40 ( 9 ) 2409 - 22 2010.09

ISSN 0014-2980

Th17 cells and Th1 cells coordinate to play a critical role in the formation of inflammatory bowel diseases. To examine how Th17 and Th1 cells are regulated at inflammatory sites, we used Th1-dominant CD4(+)CD45RB(high) T cell-transferred RAG-2(-/-) and Th1/Th17-mixed IL-10(-/-) mice. Interestingly, not only did colitic RAG-2(-/-) mice that were parabiosed with WT mice show significant amelioration of colitis, but amelioration of disease was also observed in those parabiosed with colitic IL-10(-/-) mice. To assess the interference between Th1 and Th17 colitogenic T cells, we co-transferred colitogenic CD4(+) T cells from the lamina propria (LP) of CD4(+)CD45RB(high) T cell-transferred RAG-2(-/-) mice and IL-10(-/-) mice into RAG-2(-/-) mice. Surprisingly, the co-transferred RAG-2(-/-) mice showed a vast cellular infiltration of LP CD4(+) T cells similar to that seen in RAG-2(-/-) mice re-transferred with the cells from colitic RAG-2(-/-) mice alone, but the co-transferred RAG-2(-/-) mice did not have the wasting symptoms, which are also absent in RAG-2(-/-) mice transferred with cells from colitic IL-10(-/-) mice alone. Furthermore, the percentages of Th1 and Th17 cells originating from IL-10(-/-) mice and those of Th1 cells originating from colitic RAG-2(-/-) mice were all significantly decreased in the co-transferred mice as compared with the singly-transferred paired RAG-2(-/-) mice, suggesting that Th1 and Th17 cells are in competition, and that their orchestration results in a merged clinical phenotype of the two types of murine colitis.

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Monocyte chemoattractant protein-1 contributes to gut homeostasis and intestinal inflammation by composition of IL-10-producing regulatory macrophage subset

Takada, Y., Hisamatsu, T., Kamada, N., Kitazume, M. T., Honda, H., Oshima, Y., Saito, R., Takayama, T., Kobayashi, T., Chinen, H., Mikami, Y., Kanai, T., Okamoto, S. and Hibi, T.

J Immunol 184 ( 5 ) 2671 - 6 2010.03

ISSN 0022-1767

Lamina propria macrophages (LPMs) spontaneously produce large amounts of anti-inflammatory IL-10 and play a central role in regulation of immune responses against commensal bacteria. MCP-1 is a chemokine that plays an important role in recruitment of monocytes and macrophages to inflamed tissues. We demonstrated that, in addition to IL-10, LPMs produced large amounts of MCP-1, even in a steady state. MCP-1 deficiency caused impaired IL-10 production by LPMs and led to exacerbation of dextran sulfate sodium-induced acute colitis. As an explanation of this impaired IL-10 production by LPMs, we found that LPMs could be separated into two subsets with distinct side-scattered properties, namely LPM1 (CD11b(+)F4/80(+)CD11c(-)SSC(hi)) and LPM2 (CD11b(+)F4/80(+)CD11c(-)SSC(lo)). Unlike LPM1, the LPM2 subset migrated in response to MCP-1 and produced a larger amount of IL-10 in response to commensal bacteria. LPMs isolated from MCP-1-deficient mice produced less IL-10 as a consequence of the lack of the MCP-1-dependent LPM2 population. This imbalanced composition in LPM population may be involved in the susceptibility to DSS-induced colitis in MCP-1-deficient mice. Our results suggest that endogenous MCP-1 contributes to the composition of resident LPM subsets in the intestine. Moreover, MCP-1-dependent LPM2 subset may play an important role in maintenance of gut homeostasis in the steady state, and in the termination of excess inflammatory responses in the intestine, by producing IL-10.

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Critical role of class IA PI3K for c-Rel expression in B lymphocytes

Matsuda, S., Mikami, Y., Ohtani, M., Fujiwara, M., Hirata, Y., Minowa, A., Terauchi, Y., Kadowaki, T. and Koyasu, S.

Blood 113 ( 5 ) 1037 - 44 2009.01

ISSN 0006-4971

The fact that the Xid mutation of Btk impairs the ability of pleckstrin homology domain of Btk to bind phosphatidylinositol-(3,4,5)-trisphosphate, a product of class IA phosphoinositide-3 kinases (PI3Ks), has been considered strong evidence for the hypothesis that Btk functions downstream of PI3Ks. We demonstrate here that the Xid mutation renders the Btk protein unstable. Furthermore, class IA PI3K- and Btk-deficient mice show different phenotypes in B-cell development, collectively indicating that PI3Ks and Btk differentially function in BCR signal transduction. Nevertheless, both PI3K and Btk are required for the activation of NF-kappaB, a critical transcription factor family for B-cell development and function. We demonstrate that PI3Ks maintain the expression of NF-kappaB proteins, whereas Btk is known to be essential for IkappaB degradation and the translocation of NF-kappaB to the nucleus. The loss of PI3K activity results in marked reduction of c-Rel and to a lesser extent RelA expression. The lentivirus-mediated introduction of c-Rel corrects both developmental and proliferative defects in response to BCR stimulation in class IA PI3K-deficient B cells. These results show that the PI3K-mediated control of c-Rel expression is essential for B-cell functions.

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