Can measurement of chemokines become useful biological and functional markers of early-stage chronic pancreatitis?

Ito, Tetsuhide

doi:10.1007/s00535-006-1929-4

Cited by 27 publications

(25 citation statements)

References 33 publications

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“…[51][52][53] As a result of increased recruitment of inflammatory cells, activated mononuclear cells release profibrotic cytokines and chemokines, such as TGF-b, TNF-a and MCP-1, which in turn activate hPSCs and promote fibrosis in CP. 4,52,53 The chemokine MCP-1, one of the major monocyte chemoattractants, is highly expressed in fibroblasts in CP, induces TGF-b upregulation and is associated with the progression of pancreatic fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Ceyhan

Deucker

Demir

et al. 2009

Laboratory Investigation

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The chemokine fractalkine induces migration of inflammatory cells into inflamed tissues, thereby aggravating inflammatory tissue damage and fibrosis. Furthermore, fractalkine increases neuropathic pain through glial activation, which can be diminished by blocking of its receptor, CX3CR1, through neutralizing antibodies. As chronic pancreatitis (CP) is characterized by tissue infiltration of inflammatory cells, fibrosis, pancreatic neuritis and severe pain, the roles of fractalkine and CX3CR1 were investigated in CP (n ¼ 61) and normal pancreas (NP, n ¼ 21) by QRT-PCR, western blot and immunohistochemistry analyses. Their expression correlated with the severity of pancreatic neuritis, fibrosis, intrapancreatic nerve fiber density and hypertrophy, pain, CP duration and with the amount of inflammatory cell infiltrate immuno-positive for CD45 and CD68. To investigate the influence of fractalkine on pancreatic fibrogenesis, human pancreatic stellate cells (hPSCs) were isolated from patients with CP, incubated with fractalkine and then Collagen-1 and a-smooth muscle actin (a-SMA) expressions were measured. CX3CR1, but not fractalkine, mRNA was overexpressed in CP. In contrast, the protein levels of both CX3CR1 and fractalkine were upregulated. Neuro-immunoreactivity for fractalkine and CX3CR1 was strongest in patients suffering from severe pain and pancreatic neuritis. Long-term suffering from CP was noticeably related to increased neural immunoreactivity of fractalkine. Furthermore, fractalkine and CX3CR1 mRNA overexpressions were associated with enhanced lymphocyte and macrophage infiltration. Advanced fibrosis was associated with increased fractalkine expression, whereas in vitro fractalkine had no significant impact on collagen-1 and a-SMA expressions in hPSCs. Therefore, pancreatic fractalkine expression appears to be linked to visceral pain and to the recruitment of inflammatory cells into the pancreatic tissue and nerve fibers, with subsequent pancreatic neuritis. However, pancreatic fibrogenesis is probably indirectly influenced by fractalkine. Taken together, these novel findings suggest that CX3CR1 represents a potential novel therapeutic target to reduce inflammation and modulate pain in CP.

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Section: Discussionmentioning

confidence: 99%

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Ceyhan

Deucker

Demir

et al. 2009

Laboratory Investigation

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“…This result supported previous study results and indicated that pancreatic tissue injury and various environmental factors promote CX3CL1 expression in the whole pancreas, so that connection of membrane-bound CX3CL1 and CX3CL1 receptors of inflammatory cells in the pancreatic tissue serves as the basis of the inflammation in CP as it does in chronic hepatitis. 11,17,18,36,37 Furthermore, sheddase is essential for CX3CL1 secretion into the blood. The abundant expression of sheddase in PSCs, as in hepatic stellate cells, 34 indicates that MMP not only enhances extracellular matrix degradation but also induces inflammation by CX3CL1 secretion.…”

Section: Discussionmentioning

confidence: 99%

ERK pathway and sheddases play an essential role in ethanol-induced CX3CL1 release in pancreatic stellate cells

Uchida

Ito

Nakamura

et al. 2013

Laboratory Investigation

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The clinical course of chronic pancreatitis (CP) worsens with drinking, and pancreatic stellate cells (PSCs) have an important role in the pathogenesis of alcoholic CP. Chemokines recruit inflammatory cells, resulting in chronic pancreatic inflammation. Although serum levels of fractalkine (CX3CL1) are significantly elevated in patients with alcoholic CP, the mechanism of this elevation remains unclear. This study aims to determine the effects of cytokines, pathogen-associated molecular patterns (PAMPs), and ethanol and its metabolites on CX3CL1 secretion by PSCs. Male Wistar/Bonn Kobori (WBN/Kob) rats aged 15 to 20 weeks were used as rodent models of CP in vivo. PSCs were isolated from 6-week-old male Wistar rats. The effects of cytokines, PAMPs, and ethanol and its metabolites on chemokine production and activation of signaling pathways in PSCs in vitro were examined by real-time reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and enzyme-linked immunosorbent assay. Expression of CX3CL1 and matrix metalloprotease (MMP)-2 was increased in the pancreas of WBN/Kob rats. The rat PSCs expressed CX3CL1, MMP-2, and a disintegrin and metalloprotease domain (ADAM) 17. Cytokines and PAMPs induced CX3CL1 release and activated extracellular signal-regulated kinase (ERK), MMP-9, and ADAM17. CX3CL1 release was suppressed by specific inhibitors of ERK, MMP, and ADAM, and ERK was associated with CX3CL1 transcription. Ethanol and phorbol myristate acetate synergistically increased CX3CL1 release. Real-time PCR and western blotting confirmed the synergistic activation of ERK and ADAM17. Ethanol synergistically increased CX3CL1 release via ERK and ADAM17 activation in PSCs. In conclusion, we demonstrated for the first time that ethanol synergistically increased CX3CL1 release from PSCs at least in part through activation of ERK mitogen-activated protein kinase and ADAM17. This might be one of the mechanisms of serum CX3CL1 elevation and disease progression in patients with alcoholic CP.

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“…Recently, chemokines and cytokines have been recognized to be important factors in the progression of CP [10,11] . A preliminary study by us in a small number of CP patients showed the possibility that measurement of serum soluble type fractalkine (s-fractalkine) may be useful for diagnosing early-stage of CP [7] . Thus, in the current study, using a large number of CP patients classified by severity with a staging system, we investigated whether chemokine and cytokine levels can become useful biological and functional markers of early-stage CP, focusing particularly on monocyte chemoattractant protein-1 (MCP-1), transforming growth factor beta-1 (TGF-β1), and s-fractalkine, which are supposed to be involved in chronic inflammation.…”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, simple, indirect measurements of decreased pancreatic function do not show abnormality until CP is considerably advanced. Imaging or function tests may not reveal early CP, and the results of these tests do not necessarily correlate with each other [5][6][7][8][9] . The quest continues for useful biological and functional markers of early-stage CP.…”

Section: Introductionmentioning

confidence: 99%

Fractalkine and TGF-β1 levels reflect the severity of chronic pancreatitis in humans

Yasuda¹,

Ito²,

Oono³

et al. 2008

WJG

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AIM:To clarify whether serum chemokine and cytokine levels can become useful biological and functional markers to assess the severity of chronic pancreatitis (CP). This study aimed at clarifying whether serum chemokine and cytokine levels can become useful biological and functional markers to assess the severity of CP. METHODS: Serum monocyte chemoattractant protein-1 (MCP-1), transforming growth factor beta-1 (TGF-β1), and soluble type fractalkine (s-fractalkine) concentrations were examined in patients with CP (n = 109) and healthy controls (n = 116). Severity of disease was classified in patients with CP by a staging system. Relationships between stage-specific various clinical factors and serum MCP-1, TGF-β1, and s-fractalkine levels were investigated. Furthermore, 57 patients with non-alcoholic CP were similarly evaluated in order to exclude influence of alcohol intake. RESULTS: Patients with CP showed significant higher levels of serum TGF-β1 and s-fractalkine, but not MCP-1, compared to the controls. Serum TGF-β1 in the severe stage and s-fractalkine in the mild and the severe stage of CP significantly increased compared to those of controls. However, it was observed that both TGF-β1 and s-fractalkine levels were affected by alcohol intake. In patients with non-alcoholic CP, serum TGF-β1 showed significant increase in the moderate stage of CP, and serum s-fractalkine revealed significant increase in the early stage of CP. CONCLUSION: It is suggested that the measurement of serum F-fractalkine is useful to diagnose earlystage CP. Moreover, the combined determination of both, s-fractalkine and TGF-β1, in human sera may be helpful in evaluating the severity status of CP.

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Can measurement of chemokines become useful biological and functional markers of early-stage chronic pancreatitis?

Cited by 27 publications

References 33 publications

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

ERK pathway and sheddases play an essential role in ethanol-induced CX3CL1 release in pancreatic stellate cells

Fractalkine and TGF-β1 levels reflect the severity of chronic pancreatitis in humans

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