Faculty Profiles - MATSUKAWA Akihiro

Papers - MATSUKAWA Akihiro

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Inhibition of CCL1-CCR8 interaction prevents aggregation of macrophages and development of peritoneal adhesions Reviewed International journal

Akiyoshi Hoshino, Yuki I. Kawamura, Masato Yasuhara, Noriko Toyama-Sorimachi, Kenji Yamamoto, Akihiro Matsukawa, Sergio A. Lira, Taeko Dohi

JOURNAL OF IMMUNOLOGY 178 ( 8 ) 5296 - 5304 2007.4

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC IMMUNOLOGISTS

Peritoneal adhesions are a significant complication of surgery and visceral inflammation; however, the mechanism has not been fully elucidated. The aim of this study was to clarify the mechanism of peritoneal adhesions by focusing on the cell trafficking and immune system in the peritoneal cavity. We investigated the specific recruitment of peritoneal macrophages (PM phi) and their expression of chemokine receptors in murine models of postoperative and postinflammatory peritoneal adhesions. PM phi aggregated at the site of injured peritoneum in these murine models of peritoneal adhesions. The chemokine receptor CCR8 was up-regulated in the aggregating PN phi when compared with naive PM phi. The up-regulation of CCR8 was also observed in PM phi, but not in bone marrow-derived M phi, treated with inflammatory stimulants including bacterial components and cytokines. Importantly, CCL1, the ligand for CCR8, a product of both PM phi and peritoneal mesothelial cells (PMCs) following inflammatory stimulation, was a potent enhancer of CCR8 expression. Cell aggregation involving PM phi and PMCs was induced in vitro in the presence of CCL1. CCL1 also up-regulated mRNA levels of plasminogen activator inhibitor-1 in both PM phi and PMCs. CCR8 gene-deficient mice or mice treated with anti-CCL1-neutralizing Ab exhibited significantly reduced postoperational peritoneal-adhesion. Our study now establishes a unique autocrine activation system in PM phi and the mechanism for recruitment of PM phi together with PMCs via CCL1/CCR8, as immune responses of peritoneal cavity, which triggers peritoneal adhesions.

Overexpression of suppressor of cytokine signaling-3 in T cells exacerbates acetaminophen-induced hepatotoxicity Reviewed International journal

Kosuke Numata, Masato Kubo, Hiroyuki Watanabe, Katsumasa Takagi, Hiroshi Mizuta, Seiji Okada, Steven L. Kunkel, Takaaki Ito, Akihiro Matsukawa

JOURNAL OF IMMUNOLOGY 178 ( 6 ) 3777 - 3785 2007.3

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC IMMUNOLOGISTS

Cytokines have been implicated in the progression of acetaminophen (APAP)-induced acute liver injury. Suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling by inhibiting the JAK-STAT pathway, but their role in APAP hepatotoxicity is unknown. In this present study, we attempted to explore the role of SOCS3 in T cells in APAP-induced liver injury. Mice with a cell-specific overexpression of SOCS3 in T cells (SOCS3Tg, in which Tg is transgenic) exhibited exaggerated hepatic injury after APAP challenge, as evidenced by increased serum alanine aminotransferase levels, augmented hepatic necrosis, and decreased survival relative to the wild-type mice. Adaptive transfer of SOCS3Tg-CD4(+) T cells into T and B cell-deficient RAG-2(-/-) mice resulted in an exacerbated liver injury relative to the control. In SOCS3Tg mice, hepatocyte apoptosis was enhanced with decreased expression of antiapoptotic protein bcl-2, whereas hepatocyte proliferation was reduced with altered cell cycle-regulatory proteins. Levels of IFN-gamma and TNF-alpha in the circulation were augmented in SOCS3Tg mice relative to the control. Studies using neutralizing Abs indicated that elevated IFN-gamma and TNF-alpha were responsible for the exacerbated hepatotoxicity in SOCS3Tg mice. Activation of STATl that is harmful in liver injury was augmented in SOCS3Tg hepatocytes. Alternatively, hepatoprotective STAT3 activation was decreased in SOCS3Tg hepatocytes, an event that was associated with augmented SOCS3 expression in the hepatocytes. Altogether, these results suggest that forced expression of SOCS3 in T cells is deleterious in APAP hepatotoxicity by increasing STAT1 activation while decreasing STAT3 activation in hepatocytes, possibly through elevated IFN-gamma and TNF-alpha.

非定型奇形腫様/ラブドイド腫瘍 atypical teratoid/rhabdoid tumor (AT/RT)の１例

大森昌子, 柳井広之, 荻野哲也, 井上智, 市川智継, 松川昭博, 吉野正

診断病理 24;115-120 ( 1 ) 115 - 120 2007

Language：Japanese Publisher：(一社)日本病理学会

非定型奇形腫様/ラブドイド腫瘍(atypical teratoid/rhabdoid tumor(AT/RT))はrhabdoid cellの出現を特徴とした中枢神経に発生する胎児性腫瘍で予後はきわめて不良である。症例は生後6ヵ月、女児。頭囲の拡大、発達遅延を認め、近医にて水頭症を指摘された。腫瘍は松果体部、中脳被蓋部、第四脳室にかけて存在し、脊髄に播種性病変が存在した。組織学的に腫瘍はprimitive neuroectodermal tumor(PNET)様の小型未熟細胞の充実性増殖が主体をなし、小範囲にrhabdoid cellや索状配列を示す領域が存在した。AT/RTと診断し、腫瘍摘出後化学療法が施行されたが、5ヵ月後水頭症が悪化し死亡した。(著者抄録)

Overexpression of suppressor of cytokine signaling-5 in T cells augments innate immunity during septic peritonitis Reviewed International journal

Hiroyuki Watanabe, Masato Kubo, Kosuke Numata, Katsumasa Takagi, Hiroshi Mizuta, Seiji Okada, Takaaki Ito, Akihiro Matsukawa

JOURNAL OF IMMUNOLOGY 177 ( 12 ) 8650 - 8657 2006.12

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC IMMUNOLOGISTS

Suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling by inhibiting the JAK-STAT signal transduction pathway, but their role in innate immunity remains to be investigated. In the present study, we demonstrate that overexpression of SOCS5 in T cells augments innate immunity during septic peritonitis induced by cecal ligation and puncture (CLP). Mice with a cell-specific overexpression of SOCS5 in T cells (SOCS5 transgenic (Tg)) were resistant to the lethality relative to the wild-type (WT) mice. This was most likely due to the enhanced innate immunity in SOCS5Tg mice, as bacterial burden in SOCS5Tg mice was significantly lower than WT mice. Accumulation of neutrophils and macrophages was augmented in SOCS5Tg mice, an event that was accompanied by increased peritoneal levels of IL-12, IFN-gamma, and TNF-alpha. In vitro bactericidal activities of macrophages and neutrophils were enhanced in SOCS5Tg mice. Both neutrophils and macrophages from WT mice adopted enhanced bacterial killing activity when cocultured with CD4(+) T cells from SOCS5Tg mice, relative to CD4(+) T cells from WT mice. Adoptive transfer of SOCS5Tg-CD4(+) T cells into T- and B cell-deficient RAG-2(-/-) mice resulted in augmented leukocyte infiltration and increased peritoneal levels of IL-12, IFN-gamma, and TNF-alpha after CLP, as compared with the controls. Furthermore, CLP-induced bacterial burden in RAG2(-/-) mice harboring SOCS5Tg-CD4(+) T cells was significantly reduced relative to the controls. These findings provide evidence that intervention of SOCS5 expression in T cells affects innate immunity, which highlight a novel role of T cells during sepsis.

The neuropeptide neuromedin U promotes IL-6 production from macrophages and endotoxin shock Reviewed International journal

M Moriyama, A Matsukawa, S Kudoh, T Takahashi, T Sato, T Kano, A Yoshimura, M Kojima

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 341 ( 4 ) 1149 - 1154 2006.3

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Neuromedin U (NMU) is a neuropeptide involved in appetite, circadian rhythm, and pronociception. However, the NMU receptor NMU-R1 has been shown to be expressed in immune cells and NMU promotes mast cell-dependent inflammation. In this study, we demonstrated that NMU plays an important role in IL-6 production in macrophages. NMU-deficient mice were resistant against cecal ligation puncture- as well as LPS-induced septic shock. IL-6 but not TNF-alpha levels were markedly reduced in LPS-treated NMU-deficient mice compared with wild type mice. Both NMU and NMU-R1 were expressed in wild type peritoneal macrophages, and treatment with LPS resulted in up-regulation of NMU but down-regulation of NMU-RI expression, however, no down-regulation of NMU-RI was observed in NMU-deficient macrophages where LPS-induced IL-6 production was severely reduced. These data suggest that LPS-induced IL-6 expression is partly dependent on autocrine/paracrine activation of the NMU-NMU-R1 signals in macrophages. (c) 2006 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2006.01.075

Relationship between TNF-alpha and TUNEL-positive chondrocytes in antigen-induced arthritis of the rabbit temporomandibular joint Reviewed International journal

Y Hirota, M Habu, K Tominaga, M Sukedai, A Matsukawa, T Nishihara, J Fukuda

JOURNAL OF ORAL PATHOLOGY & MEDICINE 35 ( 2 ) 91 - 98 2006.2

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

BACKGROUND: Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labeling (TUNEL) staining is a widely accepted method for the detection of DNA fragmentation in nuclei of apoptotic cells. Tumor necrosis factor (TNF)-alpha is closely associated with changes in condylar cartilage and modulates apoptosis in various tissues including cartilage. The aim of this study was to investigate the relationship between apoptotic chondrocytes and TNF-alpha in a rabbit model of arthritis.
METHOD: Unilateral temporomandibular joint (TMJ) arthritis was induced in 20 adult New Zealand White rabbits. From 1 day to 6 weeks after the induction of arthritis, immunohistochemical analysis for TNF-alpha and TUNEL was performed.
RESULTS: In condylar cartilage, TNF-alpha-positive cells and TUNEL-positive cells were localized together. TNF-alpha-positive chondrocytes seemed to precede TUNEL-positive cells.
CONCLUSIONS: The results of the present study suggest that TNF-alpha may be involved in apoptosis and/or apoptotic necrosis of chondrocytes as TMJ arthritis progresses from the acute to chronic stage.

DOI： 10.1111/j.1600-0714.2006.00367.x

Absence of CC chemokine receptor 8 enhances innate immunity during septic peritonitis Reviewed International journal

Akihiro Matsukawa, Shinji Kudoh, Gen-ichiro Sano, Takako Maeda, Takaaki Ito, Nicholas W. Lukacs, Cory M. Hogaboam, Steven L. Kunkel, Sergio A. Lira

FASEB JOURNAL 20 ( 2 ) 302 - 304 2006.2

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：FEDERATION AMER SOC EXP BIOL

An effective clearance of microbes is crucial in host defense during infection. In the present study, we demonstrate that CC chemokine receptor 8 (CCR8) skews innate immune response during septic peritonitis induced by cecal ligation and puncture (CLP). CCR8 was expressed in resident peritoneal macrophages and elicited leukocytes during CLP in the wild-type CCR8+/+ mice. CCR8-/- mice were resistant to CLP-induced lethality relative to CCR8+/+ mice, and this resistance was associated with an augmented bacterial clearance in CCR8-/- mice. In vitro, peritoneal macrophages from CCR8-/- mice, but not neutrophils, exhibited enhanced bactericidal activities relative to those from CCR8+/+ mice. Upon stimulation with the bacterial component LPS, elevated levels of superoxide generation, lysosomal enzyme release, and nitric oxide generation, effector molecules for bacterial killing were detected in CCR8-/- macrophages relative to CCR8+/+ macrophages. In addition, CCR8-/- macrophages produced significantly higher levels than CCR8+/+ macrophages of several cytokines and chemokines known to augment bactericidal activities of leukocytes that include TNF-alpha, IL-12, macrophage-derived chemokine (MDC/CCL22), macrophage inflammatory protein (MIP)-2, and KC. Altogether, these results indicate that CCR8 may have a negative impact on host defense during septic peritonitis, providing a new paradigm for the role of CCR8 in innate immunity.

DOI： 10.1096/fj.04-1728fje

Inhibitory effects of dimethylacetyl-beta-cyclodextrin on lipopolysaccharide-induced macrophage activation and endotoxin shock in mice Reviewed International journal

H Arima, K Motoyama, A Matsukawa, Y Nishimoto, F Hirayama, K Uekama

BIOCHEMICAL PHARMACOLOGY 70 ( 10 ) 1506 - 1517 2005.11

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

The potential use of hydrophilic cycloclextrins (CyDs) as an inhibitor for lipopolysaccharide (LPS) was examined. Of the five CyDs used in this study, dimethylacetyl-beta-cyclodextrin (DMA7-beta-CyD) had greater inhibitory activity than other CyDs against the production of nitric oxide (NO) and various proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) in murine macrophages stimulated with two serotypes of LPS and lipid A. The inhibitory effect of DMA7-beta-CyD on NO production was also observed in macrophages stimulated with lipoteichoic acid (LTA), but not peptidoglycan (PGN), polyinosinic-polycytidylic acid (poly I:C) or CpG oligonucleotide (CpG-ODN). Several studies have suggested that the inhibitory effects of DMA7-beta-CyD could be ascribed to the interaction with LPS. Simultaneous administration of DMA7-beta-CyD not only intraperitoneally but also intravenously and intraperitoneal injection of aqueous solution containing LPS and D-galactosamine in murine endotoxin shock model suppressed fatality. Also, DMA7-beta-CyD decreased blood level of TNF-alpha as well as serum levels of aspartate transaminase (AST) and alanine transaminase (ALT) in mice. In conclusion, DMA7-beta-CyD may have promise as a new therapeutic agent for endotoxin shock induced by LPS. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bcp.2005.08.021

Effects of denervation on neuromuscular junctions in the thyroarytenoid muscle Reviewed International journal

Y Kumai, T Ito, A Matsukawa, E Yumoto

LARYNGOSCOPE 115 ( 10 ) 1869 - 1872 2005.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Objectives/Hypothesis. To evaluate the effects of denervation on muscle fibers and neuromuscular junctions (NMJ) of the rat thyroarytenoid (TA) muscle with a histochemical method to monitor the status of degenerative NMJ. Study Design: Quantitative assessment to monitor the status of degenerative muscle fibers and NMJ in the TA muscle. Methods: Wistar rats were killed at 6, 12, 18, and 24 hours and at 2, 4, and 10 weeks after left recurrent laryngeal nerve (RLN) transection. Hematoxylin-eosin stain was used to evaluate the atrophic changes of the TA muscle. The pre- and postsynaptic structures of the NMJ were detected histochemically. These changes were evaluated by comparing the results between the treated (T) and untreated (U) sides (T/U ratio) in the same section. Results. The atrophic changes in the TA muscle progressed gradually, and at 10 weeks, the T/U ratios of the entire muscle area and of the muscle fiber size decreased to 53.2 +/- 10.7% and 55.5 +/- 6.8%, respectively (P < .01). The number of nerve terminals decreased significantly at 18 hours (P < .01), and they disappeared completely by 24 hours. In contrast, at 10 weeks, 70.5 +/- 12.4% (P < .01) of acetylcholine receptors (AchRs) were preserved. Conclusions: In the rat TA muscle, denervation. influences the presynaptic nerve terminals more than the postsynaptic AchRs and the muscle fibers. The results could be a basis for understanding the mechanism of laryngeal denervation and reinnervation processes in animal models.

DOI： 10.1097/01.mlg.0000177076.33294.89

Stat3 in resident macrophages inflammatory response Reviewed International journal

A Matsukawa, S Kudo, T Maeda, K Numata, H Watanabe, K Takeda, S Akira, T Ito

JOURNAL OF IMMUNOLOGY 175 ( 5 ) 3354 - 3359 2005.9

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC IMMUNOLOGISTS

Inflammation is counterbalanced by anti-inflammatory cytokines such as IL-10, in which Stat3 mediates the signaling pathway. In this study, we demonstrate that resident macrophages, but not other cell types, are important targets of IL-10 in a murine model of acute peritonitis. Injection of thioglycollate i.p. induced a considerable number of neutrophils and macrophages in the peritoneum, which was significantly augmented in mice with a cell-type specific disruption of the Stat3 gene in macrophages and neutrophils (LysMcre/Stat3flox(/-) mice). The augmented leukocyte infiltration was accompanied by increased peritoneal levels of TNF-alpha, MIP-2, KC chemokine (KC), and MCP-1/CCL2. Stat3 was tyrosine phosphorylated in peritoneal resident macrophages as well as infiltrating leukocytes in the littermate controls, suggesting that Stat3 in either or both of these cells might play a regulatory role in inflammation. The peritoneal levels of TNF-alpha, MIP-2, KC, and MCP-1 were similarly elevated in LysMcre/Stat3(flox/)-mice rendered leukopenic by cyclophosphamide treatment as compared with the controls. Adoptive transfer of resident macrophages from LysMcre/Stat3(flox/-) mice into the control littermates resulted in increases in the peritoneal level of TNF-alpha, MIP-2, KC, and MCP-1 after i.p. injection of thioglycollate. Under these conditions, control littermates harboring LysMcre/Stat3(flox/-) macrophages exhibited an augmented leukocyte infiltration relative to those received control macrophages. Taken together, these data provide evidence that resident macrophages, but not other cell types, play a regulatory role in inflammation through a Stat3 signaling pathway. Stat3 in resident macrophages appears to function as a repressor protein in this model of acute inflammation.

悪性腱鞘巨細胞腫と鑑別を要した手に発生した平滑筋肉腫の一例

川添泰弘, 薬師寺俊剛, 岩本克也, 佐藤広生, 前川剛士, 林田実, 松川昭博

整形外科と災害外科 54 ( 3 ) 595 - 599 2005.9

Language：Japanese Publisher：西日本整形・災害外科学会

58歳男.近医にて1年前に右手掌軟部腫瘤に対して摘出術が施行され,4ヵ月前に局所再発に対して再度摘出術が施行され,平滑筋肉腫である腱鞘巨細胞腫と診断された.今回,再び局所に腫瘤が出現したため紹介来院となった.臨床経過・局所所見・MRI所見などより腱鞘巨細胞腫と診断し摘出術を施行した.摘出標本の病理組織学的所見と平滑筋肉腫との鑑別目的の免疫染色結果から悪性腱鞘巨細胞腫と診断された.CTによる全身検索にて肺野に多発性結節性病変を認め,肺転移と診断し化学療法を開始した.悪性腱鞘巨細胞腫と平滑筋肉腫の鑑別には免疫組織化学的検索が有用であった.手に悪性腫瘍が発生することは比較的稀であるが,術前の良性・悪性の鑑別は慎重に行うべきであるものと考えられた

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2005&ichushi_jid=J00766&link_issn=&doc_id=20050927120047&doc_link_id=10.5035%2Fnishiseisai.54.595&url=https%3A%2F%2Fdoi.org%2F10.5035%2Fnishiseisai.54.595&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Intervertebral disc cells produce tumor necrosis factor alpha, interleukin-1 beta, and monocyte chemoattractant protein-1 immediately after herniation: An experimental study using a new hernia model Reviewed International journal

M Yoshida, T Nakamura, A Sei, T Kikuchi, K Takagi, A Matsukawa

SPINE 30 ( 1 ) 55 - 61 2005.1

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Study Design. A new hernia model that simulates human disc herniations was developed in rabbits. The herniated discs were examined by gross appearance and histology and production of tumor necrosis factor alpha, interleukin-1beta, and monocyte chemoattractant protein-1 was investigated.
Objectives. To clarify the early mechanism of spontaneous herniated disc resorption.
Summary of Background Data. Macrophage infiltration in herniated discs is essential for disc resorption. However, surgically removed human herniated disc tissues and existing animal hernia models are not suitable for analyzing the mechanism of macrophage infiltration. Recently, we have demonstrated that intervertebral disc cells are capable of producing monocyte chemoattractant protein-1, a potent macrophage chemoattractant, after stimulation with tumor necrosis factor alpha and interleukin-1beta.
Methods. Intervertebral disc herniations were surgically developed in rabbits using a new technique. The herniated discs were excised at appropriate time intervals after the surgery, and the size and histologic findings were examined. Expressions of tumor necrosis factor alpha, interleukin-1beta, and monocyte chemoattractant protein-1 in herniated discs were investigated immunohistochemically.
Results. A new rabbit model of disc herniation was established. The herniated discs spontaneously reduced in size by 12 weeks postsurgery. Infiltrating cells, mainly composed of macrophages, were observed from day 3. Immunohistochemically, intervertebral disc cells in the herniated discs produced tumor necrosis factor alpha and interleukin-1beta on day 1, followed by monocyte chemoattractant protein-1 on day 3.
Conclusions. The new hernia model appears to be very useful for studying herniated disc resorption. Intervertebral disc cells may produce inflammatory cytokines/chemokine immediately after the onset of disc herniation, possibly triggering subsequent macrophage infiltration that leads to disc resorption.

Chief cell hyperplasia with structural and nuclear atypia: a variant of fundic gland polyp Reviewed International journal

A Matsukawa, R Kurano, T Takemoto, M Kagayama, T Ito

PATHOLOGY RESEARCH AND PRACTICE 200 ( 11-12 ) 817 - 821 2005

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：URBAN & FISCHER VERLAG

A case of an unusual variant of fundic gland polyp (FGP) composed of chief cell hyperplasia with structural and nuclear atypia in an 87-year-old woman is presented. Gastrointestinal endoscopy revealed a sessile polyp in the cardia/corpus transition zone and a polypoid lesion in the fundus. Histologically, the polyp in the cardia/corpus showed a typical appearance of FGP, while that in fundus demonstrated a tumorous lesion composed of irregular branched tubules with nuclear stratification. Despite the structural distortion and nuclear atypia, mitotic figures were absent and MIB-1 positive cells were less than 3%. Immunohistochemically, the cytoplasms of the tubules were negative for gastric mucin and Muc-5AC glycoprotein, but mostly positive for pepsinogen-I, indicating that the proliferated glands consisted mainly of chief cells, not mucous cells. Parietal cells were occasionally found in the glands. At the periphery of the lesion, microcysts composed of parietal cells, chief cells, and mucous cells had developed. Altogether, the polyp in the fundus was diagnosed as an unusual variant of FGP with chief cell hyperplasia. This FGP should be differentiated from tubular adenocarcinoma. Proliferation of chief cells with occasional parietal cells is critical for the differential diagnosis. (c) 2004 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.prp.2004.10.005

Innate immune response in Th1- and Th2-dominant mouse strains Reviewed International journal

H Watanabe, K Numata, T Ito, K Takagi, A Matsukawa

SHOCK 22 ( 5 ) 460 - 466 2004.11

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

C57BL/6 and BALB/c mice are prototypical Th1- and Th2-type mouse strains, respectively. In the present study, we attempted to characterize the innate immune response of macrophages from these mouse strains. Macrophages from C57BL/6 mice produced higher levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-12 than those from BALB/c mice after stimulation with macrophage-activating lipopeptide-2 (MALP-2, a synthetic TLR-2 ligand) or lipopolysaccharide (LPS, a TLR-4 ligand). The augmented IL-12 production by C57BL/6 macrophages increased interferon-gamma and, in contrast, decreased IL-13 production by CD4+ T cells. On stimulation with MALP-2 or LIPS, C57BL/6 macrophages produced lysosomal enzyme and nitric oxide, effector molecules for bacterial killing, whereas BALB/c macrophages did not. Bactericidal activity of BALB/c macrophages was impaired relative to C57BL/6 macrophages when cells were infected with live bacteria in vitro. In a murine model of septic peritonitis induced by cecal ligation and puncture (CLP), BALB/c mice failed to facilitate bacterial clearance relative to C57BL/6 mice despite an augmented peritoneal leukocyte infiltration that was associated with increased peritoneal levels of cytokines/chemokines. BALB/c mice exhibited increased plasma and hepatic levels of cytokines/chemokines, resulting in an exaggerated systemic inflammation as determined by acute-phase proteins. Finally, BALB/c mice were vulnerable to CILP-induced lethality relative to C57BL/6 mice. Altogether, innate immune response of macrophages is different between these mouse strains, which may affect the development of Th1 and Th2 adaptive immunity in these strains. Reduced systemic inflammatory response in C57BL/6 mice that may result from an eminent local response appears to be beneficial during sepsis.

DOI： 10.1097/01.shk.0000142249.08135.e9

Role of CC chemokine CCL6/C10 as a monocyte chemoattractant in a murine acute peritonitis Reviewed International journal

AM LaFleur, NW Lukacs, SL Kunkel, A Matsukawa

MEDIATORS OF INFLAMMATION 13 ( 5-6 ) 349 - 355 2004.10

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：CARFAX PUBLISHING

THE aim of this study was to determine the role of CC chemokine CCL6/C10 in acute inflammation. Intraperitoneal injection of thioglycollate increased peritoneal CCL6, which peaked at 4 h and remained elevated at 48 h. Neutralization of CCL6 significantly inhibited the macrophage infiltration (34-48% reduction), but not other cell types, without decreasing the other CC chemokines known to attract monocytes/macrophages. CCL6 was expressed in peripheral eosinophils and elicited macrophages, but not in elicited neutrophils. Peritoneal CCL6 level was not decreased in granulocyte-depleted mice where eosinophil influx was significantly impaired. Thus, CCL6 appears to contribute to the macrophage infiltration that is independent of other CC chemokines. Eosinophils pre-store CCL6, but do not release CCL6 in the peritoneum in this model of inflammation.

DOI： 10.1080/09629350400014172

Role of CCR4 ligands, CCL17 and CCL22, during Schistosoma mansoni egg-induced pulmonary granuloma formation in mice Reviewed International journal

C Jakubzick, HT Wen, A Matsukawa, M Keller, SL Kunkel, CM Hogaboam

AMERICAN JOURNAL OF PATHOLOGY 165 ( 4 ) 1211 - 1221 2004.10

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC

Controversy persists pertaining to the role of CCR4 ligands, namely CCL17 (or thymus and activation regulated chemokine; TARC) and CCL22 (or macrophage-derived chemokine; MDC), in Th2-type cytokine-dominated responses in the lung. Accordingly, the present study addressed the relative role of each of these CC chemokines during an evolving pulmonary granulomatous response elicited by the intrapulmonary embolization of live Schistosoma mansoni eggs into S. mansoni-sensitized mice. CCL22 protein expression peaked at day 4, but CCL17 levels were not increased significantly at any time after egg challenge. CCR4 transcript and protein expression were highest at day 8 after egg embolization and CCR4 protein was prominently expressed in macrophages surrounding S. mansoni eggs. Systemic immunoneutralization of CCL22 from the time of egg injection into S. mansoni-sensitized mice for 8 days significantly decreased CCR4 protein expression, the eosinophil content, the overall size of the egg granuloma, and its hydroxyproline content. Whole lung levels of interferon-gamma were also significantly increased at day 8 in anti-CCL22-treated mice. The systemic immunoneutralization of CCL17 had a lesser effect on all of the granuloma parameters listed above, but this antibody treatment significantly decreased granuloma hydroxyproline content to a greater extent than the anti-CCL22 antibody treatment. In addition, the immunoneutralization of CCL17 significantly increased whole lung levels of interleukin (IL)-4, IL-5, IL-13, transforming growth factor-beta, ILL-12, and tumor necrosis factor-a at day 8 after egg infusion. Thus, these studies demonstrate a major role for CCL22 and a lesser role for CCL17 during an evolving S. mansoni egg granuloma in the lung.

Wall shear modulation of cytokines in early vein grafts Reviewed International journal

ZH Jiang, SA Berceli, CL Pfahnl, LZ Wu, D Goldman, M Tao, M Kagayama, A Matsukawa, CK Ozaki

JOURNAL OF VASCULAR SURGERY 40 ( 2 ) 345 - 350 2004.8

Language：English Publishing type：Research paper (scientific journal) Publisher：MOSBY, INC

Objective: Pro-inflammatory cytokine-driven mechanisms have been implicated in vein graft failure, though little is known about the effect of hemodynamic factors and anti-inflammatory counter-regulatory mechanisms. We hypothesized that early temporal expression of the pro-inflammatory cytokine interleukin (IL)-1beta and the anti-inflammatory cytokine IL-10 proceeds by way of wall shear stress-dependent pathways in the arterializing vein graft.
Methods. Rabbits (n = 27) underwent bilateral jugular vein carotid interposition grafts, and simultaneous unilateral distal carotid branch ligation, to produce both low-flow and high-flow grafts in the same animal. Vein grafts were harvested at 1, 3, 7, 14, and 28 days and were assessed for architecture, wall shear stress, and cytokine messenger RNA levels (quantitative real-time two-step reverse transcription polymerase chain reaction).
Results. The model resulted in an immediate 90% flow reduction (P < .001, paired t test) in the vein graft on the ligated side, and a 36% increase (P = .01) in contralateral graft flow. This persisted as similar to15-fold flow differential throughout the 28-day period. The construction yielded a 15-fold differential in wall shear stress between low-flow and high-flow vein grafts (P < .001, two-way repeated measures analysis of variance). Intimal hyperplasia began by day 3, and was 6-fold more in low wall shear grafts by 28 days (230.6 +/- 35.4 mum intimal thickness vs 36.1 +/- 17.6 mum for low shear versus high shear grafts; P = .001). For both cytokines time independently affected mRNA expression (P < .001, global analysis of variance). Exposure of vein grafts to the arterial circulation markedly up-regulated IL-10 at 1 day, with significantly more induction in the low shear setting (P =.002). IL-1beta protein localized to the developing neointima at days 1 and 3. Conversely, IL-10 slowly increased until day 14, with significantly more expression in the high shear grafts (P < .001).
Conclusions. Vein graft adaptation induces early pro-inflammatory cytokine IL-1beta expression and delayed protective IL-10 expression (most notable under high shear conditions), both of which are modulated by wall shear. These differential temporal windows offer strategies for appropriately timed pro-inflammatory or anti-inflammatory therapies to interrupt pathologic vein graft adaptations. (J Vasc Surg 2004;40:345-50.)
Clinical Relevance: Neointimal hyperplasia continues to limit the durability of vein bypass grafts. Emerging evidence suggests that inflammatory mechanisms drive the neointimal hyperplasic response. This study demonstrates that specific hemodynamic forces (altered wall shear stress) differentially affect early pro-inflammatory interleukin (IL)-1beta and delayed anti-inflammatory IL-10 signaling. These distinct temporal windows for IL-1beta and IL-10 cytokine expression offer strategies for appropriately timed pro-inflammatory and anti-inflammatory therapies to interrupt pathologic vein graft adaptations.

DOI： 10.1016/j.jvs.2004.03.048

Up-regulated expression and activation of the orphan chemokine receptor, CCRL2, in rheumatoid arthritis. Reviewed International journal

Carole L Galligan, Wataru Matsuyama, Akihiro Matsukawa, Hiroshi Mizuta, David R Hodge, O M Zack Howard, Teizo Yoshimura

Arthritis and rheumatism 50 ( 6 ) 1806 - 14 2004.6

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory condition characterized by a cellular influx and destruction of the joint architecture. Chemokines characteristically regulate leukocyte recruitment and activation. Chemokine (CC motif) receptor-like 2 (CCRL2) is an orphan receptor with homology to other CC chemokine receptors. We undertook this study to examine CCRL2 expression in RA, cytokine regulation of expression, and the source of a putative ligand in an attempt to determine the role of this receptor during inflammation. METHODS: Expression of CCRL2 on joint-infiltrating leukocytes was examined by immunocytochemistry. In vitro studies evaluated CCRL2 expression in primary neutrophils using Northern and Western blotting and reverse transcriptase-polymerase chain reaction. HEK 293 cells expressing two splice variants of CCRL2 (HEK/CCRL2A or HEK/CCRL2B) were generated with a retroviral expression system, and their migration in response to fractions of synovial fluid (SF) from RA patients was examined using a 48-well chamber. RESULTS: CCRL2 expression was observed on all infiltrating neutrophils and on some macrophages obtained from the SF of 5 RA patients. In vitro studies of primary neutrophils revealed that CCRL2 messenger RNA (mRNA) was rapidly up-regulated following stimulation with lipopolysaccharide (1 microg/ml) or tumor necrosis factor (5 ng/ml). The mRNA for both CCRL2A and CCRL2B were expressed in cytokine-stimulated neutrophils. Cells expressing either of these splice variants migrated in response to a fraction of RA SF. CONCLUSION: CCRL2 expression is up-regulated on synovial neutrophils of RA patients. Inflammatory products present in the SF activate this receptor, indicating that CCRL2 is a functional receptor that may be involved in the pathogenesis of RA.

Upregulated expression and activation of the orphan chemokine receptor, CCRL2, in rheumatoid arthritis Reviewed

C Galligan, W Matsuyama, A Matsukawa, H Mizuta, DR Hodge, OMZ Howard, T Yoshimura

FASEB JOURNAL 18 ( 4 ) A469 - A469 2004.3

Involvement of tumor necrosis factor-alpha and interleukin-8 in antigen-induced arthritis of the rabbit temporomandibular joint Reviewed International journal

M Sukedai, K Tominaga, M Habu, A Matsukawa, T Nishihara, J Fukuda

JOURNAL OF ORAL PATHOLOGY & MEDICINE 33 ( 2 ) 102 - 110 2004.2

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL MUNKSGAARD

BACKGROUND: In temporomandibular joint (TMJ) arthritis, knowledge is limited about the source of the inflammatory mediators. The aim of this study was to investigate the immunohistochemical role of tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) in the development of the antigen-induced arthritis of the rabbit TMJ.
METHODS: Unilateral TMJ arthritis was induced in 28 adult rabbits. From 6 h to 6 weeks after induction of arthritis, the topology of TNF-alpha and IL-8 was observed.
RESULTS: Positive reaction for TNF-alpha of synovial cells was observed within 3 days after induction and at 3 weeks after induction. TNF-alpha positive vascular endothelial cells and chondrocytes were identified throughout the observation period. IL-8 was detected only during the acute stage.
CONCLUSIONS: The cytokines TNF-alpha and IL-8 were observed in specific cells depending on the stage. TNF-alpha was particularly related with angiogenesis and cartilage destruction and IL-8 was involved in the acute stage of inflammation.

DOI： 10.1111/j.1600-0714.2004.00008.x

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