Mikihiko Yasuda, Tetsuhide Ito, Takamasa Oono, Ken Kawabe, Toyoma Kaku, Hisato Igarashi, Taichi Nakamura, Ryoichi Takayanagi, Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Author contributions: Yasuda M, Ito T, Kawabe K, Igarashi H and Takayanagi R designed research; Yasuda M, Oono T and Kaku T performed the research; Yasuda M and Nakamura T analyzed the data; Yasuda M and Ito T wrote the paper; Yasuda M and Ito T revised the paper.
Supported by The Research Committee of Intractable Diseases of the Pancreas, provided by the Ministry of Health, Labour, and Welfare, Japan, No. 50253448; Grant from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (20590808, Ito T)
Correspondence to: Tetsuhide Ito, MD, PhD, Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Telephone: +81-92-6425285 Fax: +81-92-6425287
Received: June 14, 2008 Revised: August 11, 2008
Accepted: August 18, 2008
Published online: November 14, 2008
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-b1), 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-b1, 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-b1 and s-fractalkine, but not MCP-1, compared to the controls. Serum TGF-b1 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-b1 and s-fractalkine levels were affected by alcohol intake. In patients with non-alcoholic CP, serum TGF-b1 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 early-stage CP. Moreover, the combined determination of both, s-fractalkine and TGF-b1, in human sera may be helpful in evaluating the severity status of CP.
© 2008 The WJG Press. All rights reserved.
Key words: Chronic pancreatitis; Transforming growth factor beta-1; Soluble fractalkine; Monocyte chemoattractant
Peer reviewer: Jose Sahel, Professor, Hepato-gastroenterology, Hospital sainti Marevenite, I270 Boolevard AE Sainti Margrenise, Marseille 13009, France
Yasuda M, Ito T, Oono T, Kawabe K, Kaku T, Igarashi H, Nakamura T, Takayanagi R. Fractalkine and TGF-b1 levels reflect the severity of chronic pancreatitis in humans. World J Gastroenterol 2008; 14(42): 6488-6495 Available from: URL: http://www.wjgnet.com/1007-9327/14/6488.asp DOI: http://dx.doi.org/10.3748/wjg.14.6488
Chronic pancreatitis (CP) is a chronic clinical disorder characterized by irreversible damage to the pancreas, the development of histologic evidence of inflammation and fibrosis, and eventually the destruction and permanent loss of exocrine and endocrine tissue[1-4]. Furthermore, patients with long-standing CP are also at a markedly increased risk of developing pancreatic cancer. 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[5-9]. The quest continues for useful biological and functional markers of early-stage CP. 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. 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-b1), and s-fractalkine, which are supposed to be involved in chronic inflammation.
MATERIALS AND METHODS
One hundred nine patients with CP (63 males and 46 females; age range, 25-81 years; mean, 56.8 years) who fulfilled clinical diagnostic criteria for CP by the Japan Pancreas Society and 116 healthy controls (69 males and 47 females; age range, 26–93 years; mean, 56.5 years) were selected for this study. Patients and healthy controls with recent inflammatory diseases, e.g. infectious diseases, chronic hepatitis, or substantial alcohol consumption were excluded. The study protocol was approved by the ethics committee at Kyushu University.
CP patients were classified according to a staging system reported previously (Table 1)[12-14]. The staging system comprises 6 parameters: exocrine pancreatic function (scored 0-3), pancreatic imaging tests by endoscopic retrograde cholangiopancreatography (ERCP; scored 0-4), glucose metabolism (scored 0-4), pain (scored 0-4), alcohol intake (scored 0-2), and complications associated with CP (scored 0-2). The CP is then subclassified, according to a total score from these 6 grading factors, into mild (total score, 0-3), moderate (total score, 4-7), and severe (total score, ≥ 8). The number of patients with mild, moderate, or severe disease was 36 (33.0%), 49 (45.0%), and 24 (22.0%), respectively (Table 2). We analyzed whether each grading factors and severity of CP are related with serum MCP-1, TGF-β1 and s-fractalkine.
Enzyme-linked immunosorbent assays (ELISAs) were used to determine serum MCP-1, TGF-b1, and s-fractalkine concentrations. Samples were examined with commercial kits according to the manufacturers’ instructions; human MCP-1, human TGF-b1 (Biosource, Camarillo, CA), and s-fractalkine (R&D systems, Minneapolis, MN). MCP-1 and TGF-b1 assays were run according to the protocol that was recommended in the kit. S-fractalkine was measured according to the protocol mentioned below. S-fractalkine was assessed using the basic components required by the manufacturer, and briefly, for the plate preparation, 4 mg/mL of mouse antibody to human fractalkine was used as the capture antibody with 96 well low-cell-binding EIA plates (Nunc, Roskilde, Denmark) in an overnight incubation at 25℃. Next, the plate was blocked with phosphate buffer saline (PBS) containing 10% fetal bovine serum (Invitrogen, Auckland, New Zealand), biotinylated mouse antibody to human fractalkine (500 mg/mL) was added after serum samples and standard, and were incubated for two hours at 25℃. Recombinant human fractalkine (R&D systems) was used as a standard. After that, the plate was incubated with streptavidin conjugated to horseradish peroxidase (HRP) for 20 min at 25℃ in the dark. Finally, antibody complex was detected by base on the formation of the avidin-biotin complex, and the color was developed with tetramethylbenzidine (TMB) solution by incubating for 30 min at 25℃ in the dark. Absorbance was read at 450 nm/570 nm.
Statistical analysis was performed using the non-parametric Mann-Whitney U test. P values less than 0.05 were considered significant. Pearson’s correlation analysis was used to calculate correlations between the data.
Serum MCP-1, TGF-b1, and s-fractalkine concentrations in patients with CP (Figure 1)
Serum MCP-1 levels in patients with CP were not significantly elevated. On the other hand, serum TGF-b1 levels in patients with CP were significantly higher than those of healthy controls (P = 0.029). Furthermore, s-fractalkine levels in CP were also significantly increased when compared to those of healthy controls (P = 0.011). Thus, we next analyzed whether specific grading factors as pancreatic imaging tests, exocrine function, glucose metabolism, pain, alcohol intake, or complications and severity of CP are related to serum MCP-1, TGF-b1, and s-fractalkine concentrations.
Serum MCP-1, TGF-b1, and s-fractalkine concentrations in relation to the severity stage of CP (Figure 2)
First, we examined the MCP-1, TGF-b1, and s-fractalkine levels in each stage of severity. Serum TGF-b1 levels in the severe stage of CP were significantly higher than in healthy controls (P = 0.008). On the contrary, serum s-fractalkine levels in the mild and in the severe stage of CP were significantly elevated compared to healthy controls (P = 0.004 and P = 0.046, respectively). However, the serum MCP-1 level didn’t significantly increase for each stage of severity.
Serum MCP-1, TGF-b1, and s-fractalkine concentrations in relation to imaging test scores in patients with CP (Figure 3)
Serum of MCP-1, TGF-b1, and s-fractalkine levels were analyzed regarding imaging scores. Serum TGF-b1 levels in patients with CP revealed a score of > 3 in pancreatic imaging tests and was found to be significantly enhanced when compared to healthy controls (P = 0.0001). On the other hand, serum s-fractalkine levels in patients with a score of 1 and a score of ≥ 3 were significantly elevated when compared to healthy controls (P = 0.010 and P = 0.041, respectively). However, no relationship was found between serum MCP-1 levels and any level of the imaging tests.
Serum MCP-1, TGF-b1, and s-fractalkine concentrations in relation to exocrine function test scores in patients with CP (Figure 4)
Serum TGF-b1 levels in patients with an exocrine function score ≥ 2 were significantly higher than in healthy controls (P = 0.042). In contrast, serum s-fractalkine was significantly elevated in patients with an exocrine function score of 0 compared to healthy controls (P = 0.030). However, no significant relationship was observed between serum MCP-1 levels and the exocrine function test.
Serum MCP-1, TGF-b1, and s-fractalkine concentrations for each score of alcohol intake in patients with CP (Figure 5)
Serum TGF-b1 and s-fractalkine levels in patients with an alcohol intake score of ≥ 1 were significantly higher than in healthy controls (P = 0.018 and P = 0.010, respectively). Serum MCP-1 levels, in contrast, appeared not to be related to alcohol consumption.
Analysis of serum MCP-1, TGF-b1, and s-fractalkine concentrations on other factors in patients with CP
Finally, serum MCP-1, TGF-b1, and s-fractalkine concentrations were analyzed in relationship to other grading factors. However, we did not observe any significant relation among them. Furthermore, serum MCP-1, TGF-b1, and s-fractalkine levels did not correlate with each other. Moreover, MCP-1, TGF-b1, and s-fractalkine levels also did not correlate with age, sex, or serum pancreatic enzymes (p-amylase and lipase).
Serum TGF-b1 concentrations in non-alcoholic CP
In order to assess the influence of alcohol intake, we next focused on 57 patients with non-alcoholic CP. In the classification of severity for CP, patients with CP in the moderate stage alone showed a significant increase in serum TGF-b1 compared to healthy controls (P = 0.039, Figure 6A). In the classification of imaging tests and exocrine function tests, patients with CP revealing a moderate progressive stage tended to have an increase in serum TGF-b1 (Figure 6B and C).
Serum s-fractalkine concentrations in non-alcoholic CP
Similarly, we examined serum s-fractalkine in patients with non-alcoholic CP. In the classification of severity and pancreatic imaging tests, patients with CP in a mild stage alone and with a score of 1 alone showed a significant increase in serum s-fractalkine compared to healthy controls (P = 0.026 and P = 0.025, respectively; Figure 7A and B). Serum s-fractalkine didn’t have a tendency for the exocrine function test (Figure 7C).
Recently, the impact of chemokines and cytokines have been recognized in the progression of chronic inflammatory diseases. However, until now, there are only few reports related to the serum chemokines and cytokines levels in patients with pancreatic diseases, especially CP. Therefore, in the present study, we examined serum MCP-1, TGF-b1, and s-fractalkine concentrations that are supposed to be involved in the progression of chronic inflammatory diseases in patients with CP. In patients with CP, TGF-b1 and s-fractalkine levels, but not MCP-1 levels, were significantly increased compared to healthy controls. CP patients were classified according to severity of disease using a staging system which is based on clinical symptoms and pancreatic functions[12-14] and analyzed for the relationship with those chemokines and cytokines in order to assess the usefulness of these mediators as biological or functional markers of CP.
MCP-1, a family member of C-C chemokines, is known to play an important role in the development of the pancreatic fibrosis in CP. Previously, we reported that MCP-1 is expressed strongly in mild to moderate stages of pancreatic fibrosis in CP model rats, and suggested MCP-1 to be a pro-fibrogenic factor for CP[16,17]. Furthermore, we showed fibrosis of CP is inhibited by blocking MCP-1[18,19]. In the present study, we thus examined whether MCP-1 might be a useful marker in CP. MCP-1 levels in patients with CP, however, were not significantly higher than in healthy controls. Also in previous reports, serum MCP-1 didn’t increase in patients with CP. Consequently, it is thought that serum MCP-1 doesn’t become a useful marker in the diagnosis of CP.
TGF-b1 is a homodimeric, multifunctional cytokine. Until now, it has been generally well understood that TGF-b1 plays an important role in the development of the pancreatic fibrosis in CP. TGF-b1 is thought to be expressed in pancreatic stellate cells (PSC) and acinar cells closer to pancreatic fibrosis, and to regulate the synthesis of collagen from PSC[23-25]. In our results, serum TGF-b1 levels of the patients with CP elevated significantly in the more severe stages of CP, especially in the group with more advanced scores in pancreatic imaging and exocrine function tests. These findings suggest that serum TGF-b1 levels tended to increase significantly in patients with more advanced CP. Previously, Su et al reported the expression of TGF-b1 in pancreatic tissue in WBN/Kob rats which is considered as a CP model, and demonstrated that expression of TGF-b1 and fibronectin showed a peak at 12 wk, whereas pancreatic fibrosis peaked at 16 wk. It was concluded that TGF-b1 may trigger fibrogenesis. Furthermore, Detlefsen et al classified the pancreatic tissue from CP patients into histological staging by an inflammatory process, and showed that TGF-b1 receptors had expressed predominantly in the early to moderate stage of pancreatic fibrosis. Given these data, we had expected that TGF-b1 levels might increase in the progressive process of pancreatic fibrosis for the present study. However, our results showed that TGF-b1 levels are elevated in patients with most advanced CP. On the other hand, interestingly, CP patients with high alcohol consumption showed a significant increase in levels of TGF-b1 (Figure 5). Concerning other organs, such as the liver and lungs, it is well known that the expression of TGF-b1 increases in the tissue of local organs from the effects of alcohol[28,29]. Therefore, in the present study, in order to clarify whether serum TGF-b1 levels might increase by TGF-b1 originated from various organs under the influence of alcohol, we focused on 57 patients with non-alcoholic CP who are not influenced by alcohol, and analyzed similarly the relationship between TGF-b1 and each factor (Figure 6). For the classification of severity of CP, patients with CP in the moderate stage alone showed a significant increase in serum TGF-b1 compared to healthy controls. Furthermore, in the classification of imaging tests and exocrine function tests, CP patients revealing a moderate progressive stage tended to have higher serum TGF-b1 levels. These results are in accordance with previous reports[26,27]. That is to say, our results support the idea that serum TGF-b1 levels might increase because the expression of TGF-b1 was elevated in the moderate stage in which fibrosis had been proceeding in a broad range of pancreatic tissue. On the other hand, serum TGF-b1 levels might decrease in severe stages because pancreatic tissue had been already replaced with fibrosis. Taken together, it is suggested that the determination of serum TGF-b1 levels might be useful to diagnose moderate stages in patients with non-alcoholic CP.
Fractalkine/CX3CL1, a family member of CX3C chemokines, has recently been reported to be expressed as a membrane-spanning adhesion molecule that can be cleaved from the cell surface to produce a soluble chemoattractant[30-33]. The expression of fractalkine has been observed on various cells such as epithelial cells or endothelial cells of several organs. Membrane-bound fractalkine (m-fractalkine) is shed by metalloproteinase, and releases s-fractalkine. M-fractalkine functions as an adhesion molecule, whereas s-fractalkine acts as a chemoattractant and recruits inflammatory cells expressing fractalkine receptors such as monocytes. In inflamed local organs, such as the liver, lungs, and the kidneys, the participation of fractalkine has been recently noted[35-40]. Furthermore, increased s-fractalkine serum levels have been reported for patients with various chronic inflammatory diseases[40-44]. However, until now, there are no reports related to fractalkine in pancreatic inflammatory diseases. In the present study, we measured s-fractalkine in the serum of patients with CP. We found serum s-fractalkine levels to be significantly elevated in patients with CP. In classification of severity and pancreatic imaging tests, serum s-fractalkine levels showed significant bisferious increase in mild and severe stages. In classification of the exocrine function tests, serum s-fractalkine levels increased in mild stages alone. On the other hand, CP patients with high alcohol consumption showed a significant increase in s-fractalkine levels, similar to those of TGF-b1 (Figure 5). Since the relationship between alcohol and fractalkine was still unclear in organs, including the pancreas, we focused on 57 patients with non-alcoholic CP, and analyzed the relationship between s-fractalkine and each factors, similar to TGF-b1 (Figure 7). In classification of severity and pancreatic imaging tests, only patients with CP in the mild stage alone showed a significant increase in serum s-fractalkine compared to healthy controls. Thus, in patients with non-alcoholic CP, the measurement of serum s-fractalkine may be useful biological and functional markers to diagnose early-stage CP.
In conclusion, it is suggested that the measurement of serum TGF-b1 may be available to diagnose moderate stage of non-alcoholic CP, and that the measurement of serum s-fractalkine may be useful to diagnose early stages of non-alcoholic CP. Therefore, the measurement of a combination of TGF-b1 and s-fractalkine may be helpful to evaluate the status of CP.
The authors thank Mr. S E Rife and Mr. H Matsuo for their contribution to this article.
Chronic pancreatitis (CP) is a chronic clinical disorder characterized by irreversible damage to the pancreas. Unfortunately, simple, indirect measurements of decreased pancreatic function have not shown abnormality until CP is advanced. The quest continues for useful biological and functional markers of early-stage CP. Recently, the roles of chemokines and cytokines have been made clear in the progression of chronic inflammatory diseases. Similarly, chemokines and cytokines have been recognized as important factors in the progression of CP. However, until now, there are only few reports addressing serum chemokine and cytokine levels in patients with pancreatic diseases, especially CP.
Recently, it is widely accepted that pancreatic stellate cells are responsible for the progression of pancreatic fibrosis production of an extracellular matrix, chemokines and cytokines. Especially, the expression of transforming growth factor beta-1 (TGF-b1) is, prior to pancreatic fibrosis in WBN/Kob rats, supposed to be a trigger for the fibrogenic process. Monocyte chemoattractant protein-1 (MCP-1) is related to the pancreatic fibrosis in di-n-butyl tin dichloride (DBTC)-induced rats. Next, it has been reported that soluble type fractalkine (s-fractalkine) increased in the serum of patients with various chronic inflammatory diseases: Atopic dermatitis, the nervous system, lupus erythematosus, rheumatoid vasculitis, and pityriasis rosea. Therefore, the purpose is to investigate whether the determination of serum MCP-1, TGF-b1, and s-fractalkine concentration can become a useful biological and functional marker of CP using large number of CP patients classified by severity with a staging system.
Innovations and breakthroughs
Serum TGF-b1 levels of the patients with CP tended to increase in the patients with more advanced CP, whereas serum s-fractalkine levels showed bimodal increase in mild and severe stages. However, it was observed that both TGF-b1 and s-fractalkine levels were affected by alcohol intake. Thus, serum TGF-b1 showed significant increase in the moderate stage of CP, and serum s-fractalkine revealed significant increase in the early stage of CP, when removed alcoholic CP. Therefore, the measurement of serum TGF-b1 may be available to diagnose moderate stage of non-alcoholic CP, and that the measurement of serum s-fractalkine may be useful to diagnose early stages of non-alcoholic CP. The measurement of a combination of TGF-b1 and s-fractalkine may be helpful to evaluate the severity status of CP.
Patients with CP fulfilled clinical diagnostic criteria for CP by the Japan Pancreas Society and healthy control patients excluded with recent inflammatory diseases such as infectious diseases and chronic hepatitis, and a large scale of drinking were selected. We classified the CP patients into stages of severity by the modified staging system which consists of 6 grading factors. Then, we analyzed whether each grading factor (pancreatic imaging tests, exocrine function, glucose metabolism, pain, alcohol intake, complications) and severity of CP are related with serum MCP-1, TGF-b1 or s-fractalkine levels. Enzyme-linked immunosorbent assays (ELISA) were performed to quantify serum MCP-1, TGF-b1, and s-fractalkine concentrations.
The conclusion of the study is that serum s-fractalkine determination is useful at the early stage of the disease. First, the classification of severity of chronic pancreatitis seems complicated since involving 6 grading factors. Apart from the clinical course and histological stage, the staging system for CP, based on clinical symptoms and pancreatic functions has been proposed in Japan. Next, to analyze a third group, a group of “healthy” but alcoholic controls without liver or other organic disease would be interesting although they are excluded in this study. An interesting perspective of this work should be the longitudinal evolution of this maker during progression of the disease.
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