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Upregulation of TLRs and IL-6 as a marker in human colorectal cancer.

Lu CC, Kuo HC, Wang FS, Jou MH, Lee KC, Chuang JH - Int J Mol Sci (2014)

Bottom Line: CRC patients had higher levels of IL-6 (p = 0.002) and IL-8 (p = 0.038) expression than healthy volunteers did; and higher IL-6 and IL-8 expression was also found to signify a higher risk of recurrence.Treatment with 3M002 can reduce IL-6 production in vitro and may prevent CRC recurrence.Our findings provide evidence that TLR1, TLR2, TLR4 and TLR8 gene expression induce downstream IL-6 and IL-8 gene expression; detection of these expression levels can serve as a CRC marker.

View Article: PubMed Central - PubMed

Affiliation: Division of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan. cclu999@gmail.com.

ABSTRACT
Toll-like receptors (TLRs) not only form an important part of the innate immune system but also serve to activate the adaptive immune system in response to cancer. Real-time PCR; immunohistochemical stain and Western blotting analyses were performed to clarify molecular alterations in colorectal cancer (CRC) patients. We identified Toll-like receptor 1 (TLR1), TLR2, TLR4 and TLR8 gene expression levels and downstream gene, i.e., interleukin-6 (IL-6), IL-8, interferon-α (IFN-α) and myeloid differentiation primary-response protein-88 (MyD88), expression levels in CRC patients and in cancer cell lines. CRC tissues have higher TLR1, TLR2, TLR4, TLR8, IL-6 and IL-8 gene expression levels than do the normal colon mucosa (p < 0.05). TLR2 expression varied in different cell types (mucosa and lymphocytes). There was no difference in the MyD88 and IFN-α gene expression levels between cancerous and normal colon mucosa. CRC patients had higher levels of IL-6 (p = 0.002) and IL-8 (p = 0.038) expression than healthy volunteers did; and higher IL-6 and IL-8 expression was also found to signify a higher risk of recurrence. CL075 (3M002) treatments can reduce the production of IL-8 in different cancer cell lines. The signaling pathway of TLRs in cancer tissue is different from that in normal cells; and is MyD88-independent. Higher expression levels of TLR1, TLR2, TLR 4 and TLR 8 mRNA were related to upregulation inflammatory cytokines IL-6 and IL-8 gene expression in tissue and to the upregulation of IL-6 in blood. The concentration of IL-6 in serum can be used as an indicator of the possibility of CRC recurrence. Treatment with 3M002 can reduce IL-6 production in vitro and may prevent CRC recurrence. Our findings provide evidence that TLR1, TLR2, TLR4 and TLR8 gene expression induce downstream IL-6 and IL-8 gene expression; detection of these expression levels can serve as a CRC marker.

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ELISA analysis IL-6 and IL-8 of colorectal cancer (CRC) patients and healthy volunteers (*p < 0.05).
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ijms-16-00159-f004: ELISA analysis IL-6 and IL-8 of colorectal cancer (CRC) patients and healthy volunteers (*p < 0.05).

Mentions: The data from the ELISA showed that CRC patients had higher levels of IL-6 concentration that was adjusted for the age difference (0.9467 ± 0.11 vs. 0.2499 ± 0.14; p = 0.002). Seventeen of the CRC patients who were in stages II and III had significantly higher IL-8 gene expression than healthy volunteers, considered to be free of malignancy and inflammatory colon mucosa (log IL-8: 1.035 ± 0.15 vs. 0.596 ± 0.13; p = 0.038) (Figure 4). There was also a statistically significant difference in the IL-6 values between those with (n = 6) and those without (n = 11) recurrences (1.3 ± 0.32 vs. 0.64 ± 0.11; p = 0.031) at the six-month follow-up point (Figure 5). The statistical data also showed a significant difference even when 10 pg/mL of IL-6 was used as a cutoff point (p = 0.028). On the other hand, IL-8 ELISA data were classified into two groups using a cutoff value of 100 pg/mL. Five patients had higher IL-8 (>100 pg/mL), and one of them had fecal peritonitis. One was at stage IV with liver metastasis, and the others had recurrences, including two pulmonary metastases and one liver metastasis. This contrasted with patients with low levels of IL-8 (<100 pg/mL) expression who had an uneventful postoperative course and no recurrence at the 36-month follow-up point (p = 0.0229).


Upregulation of TLRs and IL-6 as a marker in human colorectal cancer.

Lu CC, Kuo HC, Wang FS, Jou MH, Lee KC, Chuang JH - Int J Mol Sci (2014)

ELISA analysis IL-6 and IL-8 of colorectal cancer (CRC) patients and healthy volunteers (*p < 0.05).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4307241&req=5

ijms-16-00159-f004: ELISA analysis IL-6 and IL-8 of colorectal cancer (CRC) patients and healthy volunteers (*p < 0.05).
Mentions: The data from the ELISA showed that CRC patients had higher levels of IL-6 concentration that was adjusted for the age difference (0.9467 ± 0.11 vs. 0.2499 ± 0.14; p = 0.002). Seventeen of the CRC patients who were in stages II and III had significantly higher IL-8 gene expression than healthy volunteers, considered to be free of malignancy and inflammatory colon mucosa (log IL-8: 1.035 ± 0.15 vs. 0.596 ± 0.13; p = 0.038) (Figure 4). There was also a statistically significant difference in the IL-6 values between those with (n = 6) and those without (n = 11) recurrences (1.3 ± 0.32 vs. 0.64 ± 0.11; p = 0.031) at the six-month follow-up point (Figure 5). The statistical data also showed a significant difference even when 10 pg/mL of IL-6 was used as a cutoff point (p = 0.028). On the other hand, IL-8 ELISA data were classified into two groups using a cutoff value of 100 pg/mL. Five patients had higher IL-8 (>100 pg/mL), and one of them had fecal peritonitis. One was at stage IV with liver metastasis, and the others had recurrences, including two pulmonary metastases and one liver metastasis. This contrasted with patients with low levels of IL-8 (<100 pg/mL) expression who had an uneventful postoperative course and no recurrence at the 36-month follow-up point (p = 0.0229).

Bottom Line: CRC patients had higher levels of IL-6 (p = 0.002) and IL-8 (p = 0.038) expression than healthy volunteers did; and higher IL-6 and IL-8 expression was also found to signify a higher risk of recurrence.Treatment with 3M002 can reduce IL-6 production in vitro and may prevent CRC recurrence.Our findings provide evidence that TLR1, TLR2, TLR4 and TLR8 gene expression induce downstream IL-6 and IL-8 gene expression; detection of these expression levels can serve as a CRC marker.

View Article: PubMed Central - PubMed

Affiliation: Division of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan. cclu999@gmail.com.

ABSTRACT
Toll-like receptors (TLRs) not only form an important part of the innate immune system but also serve to activate the adaptive immune system in response to cancer. Real-time PCR; immunohistochemical stain and Western blotting analyses were performed to clarify molecular alterations in colorectal cancer (CRC) patients. We identified Toll-like receptor 1 (TLR1), TLR2, TLR4 and TLR8 gene expression levels and downstream gene, i.e., interleukin-6 (IL-6), IL-8, interferon-α (IFN-α) and myeloid differentiation primary-response protein-88 (MyD88), expression levels in CRC patients and in cancer cell lines. CRC tissues have higher TLR1, TLR2, TLR4, TLR8, IL-6 and IL-8 gene expression levels than do the normal colon mucosa (p < 0.05). TLR2 expression varied in different cell types (mucosa and lymphocytes). There was no difference in the MyD88 and IFN-α gene expression levels between cancerous and normal colon mucosa. CRC patients had higher levels of IL-6 (p = 0.002) and IL-8 (p = 0.038) expression than healthy volunteers did; and higher IL-6 and IL-8 expression was also found to signify a higher risk of recurrence. CL075 (3M002) treatments can reduce the production of IL-8 in different cancer cell lines. The signaling pathway of TLRs in cancer tissue is different from that in normal cells; and is MyD88-independent. Higher expression levels of TLR1, TLR2, TLR 4 and TLR 8 mRNA were related to upregulation inflammatory cytokines IL-6 and IL-8 gene expression in tissue and to the upregulation of IL-6 in blood. The concentration of IL-6 in serum can be used as an indicator of the possibility of CRC recurrence. Treatment with 3M002 can reduce IL-6 production in vitro and may prevent CRC recurrence. Our findings provide evidence that TLR1, TLR2, TLR4 and TLR8 gene expression induce downstream IL-6 and IL-8 gene expression; detection of these expression levels can serve as a CRC marker.

Show MeSH
Related in: MedlinePlus