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Circulating IL-6 and neopterin concentrations link cell-mediated immunity and tumor stage in patients with gastro-intestinal adenocarcinoma: relevance to the pituitary-adrenal axis and pituitary-thyroid axis

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Pteridines
From the journal Pteridines Volume 27 Issue 1-2

Abstract

Although cortisol is a powerful modulator of the immune system and inhibits production of pro-inflammatory cytokines, adrenocorticotropic hormone (ACTH) levels do not correspond to the chronically elevated concentrations of cortisol in cancer patients. Thyroid stimulating hormone (TSH) has been shown to have an effect on immunological functions. Actually it is not known whether cortisol, TSH and IL-6 have an effect on tumor progression via modulation of cell mediated immunity in patients with gastrointestinal carcinoma. Sixty-seven gastrointestinal cancer patients and 42 cancer-free subjects with cholelithiasis as the control group, were included in the study. Serum ACTH, cortisol, TSH, thyroid hormones, IL-6, IL-10 and neopterin levels were measured. Diagnosis and pathological staging were confirmed by surgical intervention. Cortisol levels were correlated with IL-6 in cancer patients. In addition to elevated neopterin values, linear regression analysis revealed that serum neopterin was associated more strongly with the increase of cortisol rather than IL-6 levels in advanced stage carcinoma. Furthermore, neopterin also correlated with IL-6, IL-10, cortisol and TSH levels in advanced carcinoma cases. These data indicated that cortisol, IL-6 and neopterin values of cancer patients were influenced by the tumor presence and progression.

Keywords: cortisol; gastrointestinal cancer; hypothalamic-pituitary-adrenal axis; neopterin; pituitary-thyroid axis

Introduction

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is characterized by non-suppressible hypercortisolism and has been described in the presence of gastric adenocarcinoma without ectopic adrenocorticotropic hormone (ACTH) production [1]. Actually a close relationship is evident between the HPA axis, the autonomic nervous system and the enteric nervous system [2]. The degree of activation of the HPA axis is proportional to the stress. Random serum total cortisol concentrations are uniformly elevated in the critically ill patients and indicate activation of this axis [3]. Plasma ACTH concentrations are reported to be high during the early phase of any chronic critical illness. In the course of time, even though plasma ACTH levels decline gradually, serum cortisol concentrations continue to increase [4]. In these cases, although pituitary ACTH is the primary regulator of glucocorticoid secretion by adult adrenal glands, ACTH levels do not correspond to the chronically elevated concentrations of glucocorticoids [5]. Furthermore, glucocorticoids are powerful modulators of the immune system and are specifically known to inhibit production of pro-inflammatory cytokines [6]. However, in most cases, cytokines have a pivotal role in the bidirectional communication between the immune and endocrine systems [7]. In particular interleukin-6 (IL-6) is known as the main endocrine cytokine that plays the major role in the immune stimulation of the HPA axis, especially during chronic inflammatory stress [8]. Consequently, important reciprocal relationships exist between the HPA axis and cellular components of the immune system [9]. Moreover, Wang et al. showed that thyroid stimulating hormone (TSH) was utilized by dendritic cells, macrophages, and subsets of naïve peripheral T cells in immune regulation [10]. Indeed, TSH has been shown to have a variety of immune-regulating cytokine-like activities that can influence the outcome of T cell development in the thymus and intestine. Production of TSH and the expression of TSH receptors are widely but selectively distributed among the subsets of dendritic cells, monocytes and lymphocytes [11]. Therefore, TSH is not only known to regulate thyroid hormone activity and subsequent metabolic functions, but also has been shown to be produced and used by cells of the mammalian immune system [12]. In this respect, TSH is a central neuroendocrine mediator of the hypothalamus-pituitary-thyroid (HPT) axis and has been shown to affect various aspects of immunological functions [13]. Low serum levels of free triiodothyronine (FT3) with a normal-to-low free thyroxine (FT4) as well as TSH levels have been proposed as prognostic factors of bad outcome in critically ill patients [14, 15]. Moreover, it is thought that TSH has an inhibitory effect on interferon-gamma (IFN-gamma) signaling [16]. Actually, Th1-cell-released IFN-gamma has been accepted to be an important mediator of cellular immunity. IFN-gamma stimulated macrophages produce neopterin via the hydrolysis of guanosine triphosphate (GTP) by the activation of GTP cyclohydrolase-1 [17]. Patients with advanced cancers have significantly higher neopterin, which is a marker of endogenous IFN-gamma production [18]. A strong correlation is obtained between the neopterin levels and the disease severity, progression and outcome of infections with inflammatory disease [19, 20]. Cytokines can modulate an anti-tumoral response, but during chronic inflammation, they can also induce cell transformation and malignancy [21]. IL-6 is a typical pro-inflammatory cytokine and has been proposed as a biomarker of malignancy, with a high sensitivity and specificity [22]. Elevated serum levels of IL-6 have been detected in patients with systemic cancers when compared to healthy controls or patients with benign diseases [22]. Additionally, interleukin 10 (IL-10) is known to be a potent anti-inflammatory cytokine [23]. Tumor cells can also secrete IL-10, as can tumor-infiltrating macrophages [24, 25].

The association of IL-6 alterations with circulating blood cortisol levels and up-regulation of thyrotropin-releasing hormone expression are well-known findings in critically ill patients, however, no conclusive data are available for gastrointestinal cancer cases [26, 27]. In this regard it is not known whether the interactions of IL-6, cortisol, TSH and IL-10 have an effect on tumor progression via regulating the cell-mediated immunity. The aim of this study was to identify the interactions between serum neopterin, cortisol, IL-6, IL-10 and TSH levels in the progression of gastrointestinal carcinoma.

Patients and methods

Patients

One hundred and nine in-patients consecutively recruited at Gazi University, Faculty of Medicine, Department of General Surgery, were included into the study. All participants’ rights were protected and informed consent was obtained according to the Helsinki Declaration. The local Ethics Committee approved the study protocol. In order to assess the health-related comorbidities, physiological severity scores were calculated by using the physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM) analysis [28]. Patients were divided into two subgroups. Forty-two cancer-free subjects aged 55.52±1.97 years [mean±standard error of mean (SEM)] were preferentially selected as a control group and were programmed for elective laparoscopic cholecystectomy for chronic calculous cholecystitis which is an inflammatory disease accompanied by presence of gallstones in the gallbladder lumen. Sixty-seven patients with a diagnosis of gastrointestinal cancer [cancer group; 67 patients constitute gastroesophageal cancer (n=24), colorectal cancer (n=30), periampullar cancer (n=13)], aged 61.26±1.52 years, underwent elective major abdominal surgery for gastrointestinal carcinoma with curative intend; resection with lymph node dissection and convenient reconstructions were made. Cancer patients were categorized according to the American Joint Committee on Cancer (AJCC) Staging, TNM classification (Table 1); primary tumor-only group (stage 1, 2: T1-T2 or T3-T4, N0, M0; n=28), metastatic lymph node positive group (stage 3: T1-3, N1-2, M0; n=28) and locally advanced group (stage 4: T4, N1-3, M0 or any T, any N, M1; n=11).

Table 1:

Assignment of 67 patients with gastrointestinal cancer according to AJCC Cancer Staging-TNM classification after surgical intervention.

Patients characteristicsControl group (n=42)Cancer patients – stage 1, 2: T1-T2 or T3-T4, N0, M0 (n=28)Cancer patients – stage 3: T1-3, N1-2, M0 (n=28)Cancer patients – stage 4: T4, N1-3, M0 or any T, any N, M1 (n=11)
Cortisol, μg/dL10.65±0.6713.19±0.85a14.67±1.06b15.35±2.28
IL-6, pg/mL19.66±3.8728.79±6.6444.74±9.11b70.80±18.89c
Albumin, mg/dL4.45±0.054.12±0.093.99±0.08b3.84±0.15c
Neopterin, nM8.84±1.3411.92±2.0520.21±6.5920.57±7.18
Frequency of increased neopterin concentrations, %40606882

ap<0.05. Control group vs. stage 1, 2 cancer patients, bp<0.005. Control group vs. stage 3 cancer patients, cp<0.005. Control group vs. stage 4 cancer patients.

None of the subjects received hormone therapy or anti-cancer agents when they were included in this study. All patients were maintained on a free diet before admission to the hospital.

The patients who received neoadjuvant chemotherapy due to the late stage carcinoma, or who have either malnutrition, autoimmune diseases intraabdominal sepsis, cardio-pulmonary or metabolic risks, as well as the patients with pituitary and adrenal disease or known clinically significant renal or liver dysfunction were excluded from the study. Preoperative diagnosis of all patients was confirmed by the operative findings and histopathological examination of postoperative specimens. Patients with unexpected results of histopathology were also excluded.

Biochemical analysis

Peripheral blood from each individual was collected into one EDTA tube and one anticoagulant free blood collection tube, pre-operatively. The first tube was kept untreated, while the second tube was used for serum separation. The plasma and serum samples were stored in aliquots at –20°C until assayed. To avoid the confounding effect of diurnal variation of ACTH and cortisol, all baseline samples were obtained from all individuals in the early morning.

For the quantitative measurement of cortisol in serum solid-phase a competitive chemiluminescent enzyme immunoassay was used with the immulite 2000 analyzer (Siemens, USA). For the quantitative measurement of ACTH in EDTA plasma a solid-phase, two-site sequential chemiluminescent immunometric assay was used with the immulite 2000 analyzer. Serum IL-6 and IL-10 concentrations were determined using a commercially obtained immunoassay (IL-6 Quantikine assay, and IL-10 Quantikine assay R and D Systems, Abingdon, UK). The Architect chemiluminescent microparticle immunoassay (CMIA) was used for the quantitative determination of FT3, FT4 and TSH in human serum (ADVIA Centaur CP Immunoassay System, Siemens, USA). Total thyroid hormones are influenced by variations of thyroid hormone-binding proteins and albumin in seriously ill patients [29, 30]. Although serum albumin levels of our patients were above the cut-off value of 3.5 g/dL in all individuals, the mean albumin levels were found significantly reduced in gastrointestinal cancer patients (4.03±0.06 g/dL) when compared with the controls (4.45±0.05 g/dL), p=0.0001. Therefore, total 3, 5, 3′-triiodo-L-thyronine (T3) and L-thyroxine (T4) assays are less reliable, especially in critical patients. Due to their higher diagnostic performance, FT4 and FT3 measurements have superseded the total hormone assay [31]. Because of the significant decrease of serum albumin concentrations in our series of cancer patients, we measured FT3 and FT4 levels for the evaluation of thyroid functions. Additional laboratory tests including complete blood count (analyzed by flow cytometry on UnicelDxH800/Counter Cellular Analysis System, Beckman Coulter, USA), liver function tests, creatinine and other serum biochemical tests (measured colorimetrically on Cobas 8000 modular analyzer, Roche Diagnostics, USA) were undertaken to evaluate the patient’s general status (data not given).

Even though the presence of significant differences between the mean physiologic scores (p=0.035) and ages (p=0.011) of the control group and cancer group, serum creatinine levels (89.93±4.30 mg/dL for the control group and 83.66±3.31 mg/dL for cancer group) were not statistically different (p=0.339).

Serum neopterin concentrations were measured using ELISA (Neopterin ELISA Kit Company, IBL International GmbH, Germany).

Statistical analysis

Data were analyzed by using the statistical package SPSS, version 13.0 (SPSS Inc., Chicago, IL, USA). All results were expressed as the mean±SEM. After checking the data by the Kolmogorov-Smirnov test, normally distributed data were analyzed by using the independent samples t-test, and Levene’s test was used for assessing the equality of variances. Nonparametric data were compared with the Mann-Whitney U test. Differences between the medians and the relationship between two variables were evaluated with the Kruskal-Wallis test. The linearity and distribution across the regression line among variables were analyzed by linear regression tests. Correlations were assessed by using Spearman’s rho rank test or Pearson’s correlation test, where appropriate. p<0.05 was considered statistically significant.

Results

POSSUM physiologic scores of the gastrointestinal cancer patients (15.83±0.47%) were found to be significantly higher than the control group (14.66±0.49%), p=0.035. However, the physiological performance status of cancer patients did not preclude definitive surgical intervention.

Serum cortisol levels of cancer patients was increased by approximately 33% above the mean cortisol values of control group (p=0.001). Similar to changes in cortisol, circulating IL-6 concentrations were 2.2 times higher in cancer patients (p=0.002) when compared to the control group (Table 2). In addition to simultaneous increase in cortisol and IL-6 levels of patients with gastrointestinal carcinoma, linear regression analyzes revealed a highly significant positive relationship (r=0.374, p=0.005) between these parameters. In contrast to the control group, the lack of correlation between the ACTH and cortisol concentrations in cancer patients (r=–0.084, p=0.626) suggested a considerable dissociation in the HPA axis in cancer cases.

Table 2:

Characteristics of 109 patients and evaluation of gastrointestinal cancer cases vs. control subjects at diagnosis.

Patients characteristicsControl group (n=42)Gastrointestinal cancer cases (n=67)p
Age, years55.52±1.9761.26±1.520.011a
Physical performance, POSSUM score14.66±0.4915.85±0.470.103b
ACTH, pg/mL25.80±10.6034.9±7.60.412b
Cortisol, μg/dL10.65±0.6714.16±0.670.001a
FT3, pg/mL2.75±0.102.46±0.060.015a
FT4, ng/dL1.30±0.181.44±0.130.543b
TSH, μIU/mL1.35±0.121.36±0.150.972b
IL-6, pg/mL19.66±3.8743.57±6.110.002a
IL-10, pg/mL3.24±0.464.28±0.870.347b
Albumin, mg/dL4.45±0.054.02±0.060.0001a
Neopterin, nM8.84±1.3316.82±3.110.021b

p<0.05 was considered statistically significant; aMann-Whitney U test, bIndependent samples t-test (Levene’s test for equality of variances).

Although the mean FT3 values of patients with gastrointestinal cancer were significantly lower than that of control group (p=0.015), serum FT4 and TSH levels of cancer cases did not differ compared to controls (p=0.543 and p=0.972, respectively) (Table 2). Serum TSH levels also did not show any correlation with neither FT4 nor FT3 or cortisol values of cancer patients, whereas serum FT3 and cortisol levels inversely correlated with the serum TSH concentrations in control group (r=–0.430, p=0.004 and r=–0.347, p=0.026, respectively). The lack of correlation between the TSH-FT3 (r=0.182, p=0.137) and TSH-cortisol (r=–0.017, p=0.891) in the gastrointestinal cancer group indicated a distinct dissociation in the HPT axis in cancer cases. Actually, the results of the correlation analysis revealed that the cortisol response has a significant negative correlation with the TSH response [32]. Furthermore, we could not find an overall significant correlation between IL-6 and thyroid hormones. Although neopterin levels did not correlate with TSH values in both groups, neopterin concentrations of stage 4 cancer patients showed a significant positive correlation with their own TSH levels (r=0.937, p=0.0001) (Table 3).

Table 3:

Significant correlations (p<0.05) between the variables of control group vs. gastrointestinal cancer cases.

GroupVariableCorrelation coeff. sign.
Control group (n=42)Age-neopterinr=0.480, p=0.007
Cortisol-TSHr=–0.347, p=0.026
TSH-FT3r=–0.430, p=0.004
Cancer patients (n=67)Cortisol-IL6r=0.304, p=0.024
Cortisol-neopterinr=0.492, p=0.0001
IL6-neopterinr=0.303, p=0.02
IL10-Neopterinr=0.294, p=0.03
Albumin-FT3r=0.331, p=0.006
Tumor StageVariableCorrelation coeff. sign.
Stage 1-2 (n=28)TSH-FT4r=–0.430, p=0.02
Albumin-FT3r=0.538, p=0.002
Stage 3 (n=28)Cortisol-neopterinr=0.550, p=0.002
TSH-IL10r=–0.494, p=0.01
Stage 4 (n=11)Cortisol-TSHr=0.659, p=0.02
IL6-TSHr=0.628, p=0.03
Neopterin-IL6r=0.695, p=0.018
Neopterin-TSHr=0.937, p=0.0001
Neopterin-IL10r=0.631, p=0.037
Neopterin-cortisolr=0.780, p=0.005
IL6-IL10r=0.669, p=0.024
IL10-TSHr=0.690, p=0.019

Correlation coeff. sign.: r, correlation coefficient; p, significance.

Neopterin values of cancer patients were significantly higher when compared with the control group (independent samples t-test, p=0.021) (Figure 1). Evaluation of relationship between the variables proved that cortisol (p=0.001), IL-6 (p=0.002) and neopterin (p=0.04) were dependent variables. In contrast to the control group (r=–0.211, p=0.185) regression analysis showed that the cortisol levels were linearly dependent to neopterin (r=0.492, p=0.0001). Also cortisol was directly associated with IL-6 (r=0.374, p=0.005) (Figure 2). Furthermore, contrary to the control group, a significant positive correlation was found between the serum IL-6 and cortisol levels in cancer patients (r=0.304, p=0.024). Nevertheless, a weak dependency was found between IL-6 and neopterin (r=0.303, p=0.025). Lack of linear distribution across the regression line of cortisol, IL-6 and neopterin values of the control group suggested that these data were strongly influenced by the presence of gastrointestinal cancer. However, the average neopterin level of the control group was below the standard cutoff value, 10 nmol/L [33].

Figure 1: Alterations of ACTH-independent cortisol production associated with IL-6 and neopterin values. *p<0.05, control vs. cancer patients.
Figure 1:

Alterations of ACTH-independent cortisol production associated with IL-6 and neopterin values. *p<0.05, control vs. cancer patients.

Figure 2: Results of the linear regression analysis of overall gastrointestinal cancer cases and control group. p<0.05 was considered to be statistically significant. A, C, E: the graphics of gastrointestinal cancer cases, B, D, F: the graphics of control group.
Figure 2:

Results of the linear regression analysis of overall gastrointestinal cancer cases and control group. p<0.05 was considered to be statistically significant. A, C, E: the graphics of gastrointestinal cancer cases, B, D, F: the graphics of control group.

Furthermore, the comparison of the primary tumor-only group (stage 1, 2: T1-T2 or T3-T4, N0, M0; n=28) with the control group displayed no significant changes in all variables, whereas lymph node positive patients with gastrointestinal cancer had significantly higher cortisol (p=0.001) and IL-6 levels (p=0.005) than those of the control group. Cortisol and IL-6 levels also showed a significant rise in the metastatic lymph node positive group (stage 3: T1-3, N1-2, M0; n=28) (Table 1).

Additionally, cortisol-neopterin and neopterin-TSH correlations were more pronounced in the locally advanced cancer group (stage 4: T4, N1-3, M0 or any T, any N, M1; n=11), r=0.780, p=0.005 and r=0.937, p=0.0001, respectively). Also, serum IL-6 and IL-10 levels showed a significant correlation with neopterin in this subgroup (r=0.695, p=0.018 and r=0.631, p=0.037, respectively) (Table 3). However, linear regression analysis revealed that serum neopterin was influenced more strongly by the rise of cortisol level (r=0.245, p=0.0001) than increase in IL-6 levels. These findings showed that cortisol, IL-6 and neopterin values of cancer patients were influenced by the tumor progression. The overall IL-10 values of cancer cases did not differ from the control group. However, stage 3 patients showed a significant negative correlation between TSH and IL-10 (r=–0.494, p=0.01). Furthermore, in stage 4 cancer cases correlation analysis revealed that IL-10 positively related to neopterin (r=0.631, p=0.037), IL-6 (r=0.669, p=0.024) and TSH (r=0.690, p=0.019) levels.

Although there were no significant differences between the neopterin concentrations of controls and gastrointestinal cancer subgroups, the calculated frequencies of increased neopterin concentrations at diagnosis gradually increased in order of subgroups, primary tumor-only, metastatic lymph node positive and locally advanced cancer groups (Table 3). Furthermore, approximately four-fifths of the advanced cases exceeded the median values of cancer-free subjects.

Discussion

The ultimate impact of stress-induced inflammatory responses is a function of stressor exposure and physiological responses [34]. Immune and endocrine status of the patients may play an important role in cancer progression. In particular, it has been observed that abnormally high levels of cortisol and its altered circadian secretion are associated with poor prognosis in cancer patients [35]. In our study, the lack of correlation of ACTH secretion with the enhanced cortisol production displayed an unexpected ACTH-cortisol dissociation in patients with gastrointestinal carcinoma. As glucocorticoids are potently immunosuppressive, the acute or chronic stress-related hypercortisolemia may induce functional immunosuppression. During the chronic inflammation, relatively constant cytokine release into the circulation may trigger a glucocorticoid response that would especially disrupt circadian variation in cortisol levels. This may induce the glucocorticoid resistance that disrupts negative feedback-control [36]. Likewise, the findings of Lissoni et al. [35], the evidence of significantly higher concentrations of IL-6 and its correlation with cortisol production in hypercortisolemic cancer cases suggest that cancer-related enhanced cortisol production might depend on a direct adrenal stimulation by IL-6 itself. As IL-6 receptor expression is distributed into the entire adrenal gland, IL-6 may act directly on the steroid production via this receptor [37]. IL-6 has been proposed as a malignancy predictor, with sensitivity and specificity of about 60%–70% and 58%–90%, respectively [22]. In our study, circulating IL-6 concentrations were significantly associated with increased tumor stage (stage 3: p=0.005, stage 4: p=0.001) in the cancer group. These data confirm that cortisol secretion has been directed by IL-6 instead of ACTH in cancer patients. Consequently, cancer-related hypercortisolemia would seem to depend on the positive feedback mechanisms between the cortisol and IL-6. Activation of the HPA axis by pro-inflammatory cytokines results in the release of endogenous glucocorticoids, which in turn suppress innate and specific immune responses [38]. Th1 and Th2 cytokines act in conjunction with cortisol to determine the final outcome of the initial inflammatory and immune response [39]. Stepwise linear regression analysis revealed that serum neopterin alterations in overall cancer cases were strongly related to the variability of cortisol (r=0.492, p=0.0001). When neopterin overproduction is claimed as a risk factor for cancer patients [40], it appears to exclude other conditions that cause IFN-gamma and macrophage stimulation. Thus, 40% of our control group showed a higher frequency of neopterin concentrations at diagnosis (Table 4). Even though the control individuals had low-grade inflammatory reaction due to gallstone disease, their mean plasma neopterin levels were under the known cutoff value.

Table 4:

Progressive increase in neopterin production with the advancement of the stage in gastrointestinal cancer cases.

Group (n)Neopterin Median (min–max), nMFrequency of increased neopterin concentrations (%)amean±SEM, nM
Control group (n=42)6.35 (2.36–49.24)17 (40)8.84±1.34
Cancer patients – stage 1, 2 (T1-4, N0, M0) (n=28)7.85 (2.40–46.95)17 (60)11.92±2.05
Cancer patients – stage 3 (T1-3, N1-2, M0) (n=28)7.26 (2.64–163.49)19 (68)20.21±6.59
Cancer patients advanced stage – stage 4 (T4, N1-3, M0 or AnyT, AnyN, M1) (n=11)11.21 (2.44–82.29)9 (82)20.57±7.18

aFrequency was estimated by comparing with the median of the control group.

It has been suggested that JAK/STAT/SOCS-signaling pathway plays a critical role in immune response and regulation of inflammation due to its affiliation with cytokine signaling [41]. Both JAK1 and JAK2 are important for IFN-gamma and IL-6 through their shared receptor subunits, gamma chain and co-receptor glycoprotein 130. IFN-gamma and IL-6 are two important pro-inflammatory cytokines that use these receptors which are essential for cytokine signaling [42, 43]. In our study, we found a significant linear association and distribution between IL-6, cortisol and neopterin concentrations of gastrointestinal cancer patients in addition to the significant positive correlation. Although IFN-gamma values were not evaluated in this study, it is well known that neopterin synthesis is related to the stimulation by IFN-gamma [17]. Both IL-6 and IFN-gamma acts on the same receptor subunit. While IL-6 stimulating cortisol synthesis/release favors immunosupression, neopterin acts as an indicator of the cell mediated immunity. These opposite effects of two cytokines seem to be a challenge. Further, cortisol levels depend linearly on neopterin (r=0.492, p=0.0001). Also, cortisol is directly influenced by IL-6. In our study, overall IL-10 values of cancer cases did not differ from the control group. IL-6, IL-10 and neopterin levels were not correlated with FT3, FT4 and TSH except at advanced stages. While stage 3 patients showed a significant negative correlation between IL-10 and TSH, in stage 4 cancer cases, IL-10 positively related to neopterin and TSH values. Actually thyroid hormones have been also implicated in cellular transformation, tumorigenesis and metastasis, assuming particular importance in tumor induced angiogenesis [44]. Thereby, advanced-stage diseases (stage 3 and 4) constituted 58.2% of our series of cancer patients and severities of pituitary-thyroid axis and pituitary-adrenal axis dissociation may be increased with the progression of cancer. Actually, a significant correlation was found between IL-6 and FT3 or TSH in addition to the permanent TSH-FT3 dissociation in these patients in contrast to the control group. Eventually these results suggested that more reasonable consideration for dissociation of cortisol-TSH relevance in gastrointestinal cancer patients may be the presence of coincidental disorders of pituitary-thyroid axis and pituitary-adrenal axis which seem to be triggered by IL-6. IL-6 is a typical pro-inflammatory cytokine which promotes tumor growth, and might be associated with poor prognosis. Considering the clinical trials which are currently evaluating the antibodies against IL-6 or IL-6 receptor [45, 46], further prospective studies are required to establish the impacts of IL-6 and cortisol on cell-mediated immunity in cancer cases, especially in advanced cases.

Acknowledgments:

This study was supported by The Scientific and Technological Research Council of Turkey, SBAG-HD-131 (106S116).

  1. Conflict of interest statement: All authors have declared no conflicts of interest. All authors contributed to the manuscript and approved its final version.

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Received: 2015-12-3
Accepted: 2016-3-29
Published Online: 2016-5-9
Published in Print: 2016-6-1

©2016 by De Gruyter

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Articles in the same Issue

  1. Frontmatter
  2. Original articles
  3. Prolonged response to pemetrexed-based chemotherapy in a patient with peritoneal mesothelioma: a case report and review of the literature
  4. Folate, neopterin and kynurenine pathway in patients with statin therapy
  5. Detection of neopterin in tear samples
  6. Circulating IL-6 and neopterin concentrations link cell-mediated immunity and tumor stage in patients with gastro-intestinal adenocarcinoma: relevance to the pituitary-adrenal axis and pituitary-thyroid axis
  7. Lysosomes appear as the auto-fluorescent vacuoles in Dictyostelium discoideum cells
  8. Conference abstracts
  9. 35th International Winter Workshop
https://doi.org/10.1515/pterid-2015-0018
Keywords for this article
cortisol; gastrointestinal cancer; hypothalamic-pituitary-adrenal axis; neopterin; pituitary-thyroid axis
Creative Commons
BY-NC-ND 3.0

Articles in the same Issue

  1. Frontmatter
  2. Original articles
  3. Prolonged response to pemetrexed-based chemotherapy in a patient with peritoneal mesothelioma: a case report and review of the literature
  4. Folate, neopterin and kynurenine pathway in patients with statin therapy
  5. Detection of neopterin in tear samples
  6. Circulating IL-6 and neopterin concentrations link cell-mediated immunity and tumor stage in patients with gastro-intestinal adenocarcinoma: relevance to the pituitary-adrenal axis and pituitary-thyroid axis
  7. Lysosomes appear as the auto-fluorescent vacuoles in Dictyostelium discoideum cells
  8. Conference abstracts
  9. 35th International Winter Workshop
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