Ryosuke Hamano

Stimulation of alpha7 nicotinic acetylcholine receptor inhibits CD14 and the toll-like receptor 4 expression in human monocytes.

ABSTRACT The lipopolysaccharide (LPS)-receptor complex, CD14/toll-like receptor 4, is known to play a role in the immune responses during sepsis. Excessive inflammation and tumor necrosis factor (TNF)-&agr; synthesis have been reported to cause morbidity and mortality in endotoxemia and sepsis. Cell-to-cell interaction through the engagement between intercellular adhesion molecule 1, B7.1, and CD40 on monocytes and their ligands on T cells has been suggested to play a role in the inflammatory response such as TNF-&agr; and interleukin 10 production. Nicotine, with the stimulation of the nicotinic acetylcholine receptor &agr;7 subunit (&agr;7-nAChR), has now become the focus of attention because of its anti-inflammatory effects. However, little is known about the mechanism of the inhibitory effects induced by nicotine on the LPS-induced immune responses. In the present study, we found that nicotine suppressed the expression of CD14, toll-like receptor 4, intercellular adhesion molecule 1, B7.1, and CD40 on monocytes and the production of TNF-&agr;, but not interleukin 10, in human peripheral blood mononuclear cells in the presence of LPS. The actions of nicotine were reversed by a nonselective and a selective &agr;7-nAChR antagonist, mecamylamine and &agr;-bungarotoxin, respectively. Therefore, nicotine might inhibit the LPS receptor complex expression via &agr;7-nAChR, thus leading to a decrease in the adhesion molecule expression and TNF-&agr; production. Moreover, we demonstrated that a nuclear factor-&kgr;B and a p38 mitogen-activated protein kinase inhibitor mimicked the actions of nicotine in the presence of LPS. These results suggested that the nuclear factor-&kgr;B and p38 mitogen-activated protein kinase might be involved in the actions of nicotine.

Effect of nicotine on IL-18-initiated immune response in human monocytes

Nicotine is thought to inhibit the production of proinflammatory cytokines from macrophages through an anti‐inflammatory pathway that is dependent on nicotinic acetylcholine receptor α7 subunit (α7‐nAChR). IL‐18, an important proinflammatory cytokine, is reported to induce the expression of adhesion molecules on monocytes, thus enhancing cell‐to‐cell interactions with T‐cells and contributing to IL‐18‐initiated cytokine production. Accordingly, inhibition of IL‐18 suppresses systemic inflammatory responses. In the present study, we found that nicotine inhibited the IL‐18‐enhanced expression of ICAM‐1, B7.2, and CD40 on monocytes, and the production of IL‐12, IFN‐γ, and TNF‐α by PBMC. A nonselective and a selective α7‐nAChR antagonist, mecamylamine, and α‐bungarotoxin abolished the effects of nicotine, suggesting that this depends on α7‐nAChR stimulation. It is reported that nicotine induces prostaglandinE2 (PGE2) production in PBMC through the up‐regulation of cyclooxygenase (COX)‐2 expression. PGE2 is known to activate the EP2/EP4‐receptor, leading to an increase in cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity. Consistent with this, we found that COX‐2 and PKA inhibitors prevented the effects of nicotine on adhesion molecule expression and cytokine production, indicating that the mechanism of action of nicotine may be via endogenous PGE2 production.

Effects of adenosine on adhesion molecule expression and cytokine production in human PBMC depend on the receptor subtype activated

Adenosine suppresses immune responses through adenosine2A (A2A) receptors, by raising intracellular cAMP. Interleukin (IL)‐18 up‐regulates the expression of intercellular adhesion molecule (ICAM)‐1 on monocytes, leading to production of pro‐inflammatory cytokines such as IL‐12, interferon (IFN)‐γ and tumor necrosis factor (TNF)‐α by human peripheral blood mononuclear cells (PBMC). We have previously demonstrated that elevation of cAMP inhibits this IL‐18‐induced expression of adhesion molecules. In the present study, we examined the effect of adenosine on the IL‐18‐induced up‐regulation of ICAM‐1 on human monocytes and production of IL‐12, IFN‐γ and TNF‐α by PBMC.

Stimulation of adenosine A2A receptor inhibits LPS-induced expression of intercellular adhesion molecule 1 and production of TNF-α in human peripheral blood mononuclear cells

LPS stimulates CD14/Toll-like receptor (TLR) 4, leading to induce TNF-&agr; production. Cell-to-cell interaction through the engagement between intercellular adhesion molecule (ICAM) 1 on monocytes and its ligand on T cells has been suggested to play a role in the TNF-&agr; production by LPS-treated human peripheral blood mononuclear cells (PBMCs). Adenosine is reported to inhibit LPS-induced TNF-&agr; production. However, little is known about the mechanism of the inhibitory effects induced by adenosine on the LPS-induced immune responses. We found that adenosine inhibited the expression of ICAM-1 and the production of TNF-&agr; by human PBMC via adenosine A2A receptor in the presence of LPS. However, the stimulation of A1R or A3R enhanced the actions of adenosine. Adenosine had no effect on the expression of CD14 and TLR-4, suggesting that the inhibitory effects of adenosine on the LPS actions might be independent of the expression of CD14 and TLR-4. Thus, adenosine differentially regulates the expression of ICAM-1 and the production of TNF-&agr; through plural subtypes of receptors.

A Case of Resected Cholangiolocellular Carcinomaduring Treatment for Lung Cancer

A Case of Resected Cholangiolocellular Carcinoma during Treatment for Lung Cancer Cholangiolocellular carcinoma is an extremely rare malignant primary liver tumor, accounting for less than 1% of primary liver tumors. We herein report a case of cholangiolocellular carcinoma during treatment for lung cancer. A woman following up after operation for lung cancer was found to have a solitary hepatic tumor in the left lobe of the liver at an abdominal computed tomography checkup. It showed early enhancement with hypovascular area of the center in the arterial phase and enhancement contrast retention in the delayed phase. The tumor was seen as a hypointense nodule in the hepatocellular phase of EOB magnetic resonance imaging. We diagnosed liver metastasis of lung cancer with differential diagnosis of cholangiocellular carcinoma. We performed extended left lobectomy of the liver. Histological and immunohistochemistry findings were compatible with cholangiolocellular carcinoma./p>

成人鼠径ヘルニア手術症例の臨床的検討：Mesh plug 法と PROLENE hernia system の比較

To compare the results of the PROLENE hernia system (PHS) and mesh-plug technique (MPT), a retrospective study of adult patients with inguinal hernia was performed. The total number of inguinal herniorrhaphies for the past 9 years was 376, and the numbers of operative treatments by PHS, MPT and the Bassini procedure were 79, 291 and 6, respectively. There were no significant differences either in the operating time or the hospitalization days. No postoperative complications were observed in the PHS group; however, 8 complications were found among the 291 cases (2.75 %) of the MPT group (hematoma, 3 ; seroma, 2 ; testitis, 1 ; mesh infection, 2). Out of the total 376 cases, the number of initial and recurrence cases was 355 and 21, respectively, and out of the 21 recurrence cases the number of initial surgeries by Bassini and MPT was 14 and 7, respectively. Among the 21 recurrence cases there were no recurrences after PHS.

A retrospective study of the PROLENE hernia system compared with the mesh‑plug technique

To compare the results of the PROLENE hernia system (PHS) and mesh-plug technique (MPT), a retrospective study of adult patients with inguinal hernia was performed. The total number of inguinal herniorrhaphies for the past 9 years was 376, and the numbers of operative treatments by PHS, MPT and the Bassini procedure were 79, 291 and 6, respectively. There were no significant differences either in the operating time or the hospitalization days. No postoperative complications were observed in the PHS group; however, 8 complications were found among the 291 cases (2.75 %) of the MPT group (hematoma, 3 ; seroma, 2 ; testitis, 1 ; mesh infection, 2). Out of the total 376 cases, the number of initial and recurrence cases was 355 and 21, respectively, and out of the 21 recurrence cases the number of initial surgeries by Bassini and MPT was 14 and 7, respectively. Among the 21 recurrence cases there were no recurrences after PHS.

Nonfunctioning endocrine tumor of the pancreas: A case report

We report a rare case of a very large nonfunctioning endocrine tumor of the pancreas without malignant histological features. A 63-year-old woman referred for appetite loss and general fatigue was found to have a tumor in the pancreas head. Computed tomography demonstrated a well-defined pancreatic tumor 45mm in diameter with hypervascular staining in the pancreas head. Angiography showed a hypervascular tumor of the pancreas head and a dilatation of the anterior superior and posterior superior pancreaticoduodenal arteries. The preoperative diagnosis was an endocrine tumor of the pancreas, with undeniable malignancy. Pylorus-preserving pancreaticoduodenectomy was performed. The histopathological diagnosis was a benign nonfunctioning endocrine tumor of the pancreas based on immunohistochemical staining for Chromogranin A, Synaptophysin, and NSE, but not for hormones. The tumor revealed a low labeling index (<2.0%) of Ki-67 indicating its benign character. No tumor recurrence has been identified in the 18 months since surgery.