Abstract
The main regulator of anti-tumor immune response is the activity of monocytes, suggesting that the produced cytokines may have a prognostic role. This study investigates gene expression of interleukin (IL)-12-related cytokine and IL-10 in stimulated monocytes from colorectal cancer (CRC) patients. Relative quantification of IL-12A, IL-12B, IL-23A and IL-10 mRNA transcripts was performed on the third hours after stimulation by real-time qPCR. We also explored an inhibitor of JNK signaling pathway activation for the observed cytokine gene expression. A strong downregulation of IL-12B mRNA expression in CRC monocytes compared to healthy donors was observed. The rate of transcription of IL-12B in stimulated monocytes was associated with the stage of CRC. The expression of IL-12A gene in stimulated monocytes from patients with advanced was lower than early cancer. Moreover, we observed stage dependent JNK inhibition mediated reduction in IL-12A expression. The hyporesponsiveness was strongly expressed in monocytes from advanced then early stages of CRC. Expression of IL-10 mRNA was almost equally in CRC monocytes from early stages and healthy donors. We demonstrated that altered gene expression profiles of IL-12A, IL-12B, IL-23A at mRNA level in CRC monocytes was associated with tumor development and can be attributed to anticancer immune response.
Similar content being viewed by others
References
Greenlee RT, Murray T, Bolden S, Wingo PA (2000) Cancer statistics. CA Cancer J Clin 50:7–33
Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545
Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867
Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137–148
Dranoff G (2004) Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 4:11–22
Bellone G, Smirne C, Mauri F et al (2006) Cytokine expression profile in human pancreatic carcinoma cells and in surgical specimens: implication for survival. Cancer Immunol Immunother 55:684–698
Brunda MJ, Luistro L, Hendzak JA, Fountoulakis M, Garotta G, Gately MK (1995) Role of interferon-γ in mediating the antitumor efficacy of interleukin-12. J Immunother Emphas Tumor Immunol 17:71–77
Gri G, Chiodoni C, Gallo E, Stoppacciaro A, Liew F, Colombo M (2002) Antitumor effect of Interleukin (IL)-12 in the absence of endogenous IFN-γ: a role for intrinsic tumor immunogenicity and IL-15. Cancer Res 62:4390–4397
Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3:133–146
Hölscher C (2004) The power of combinatorial immunology: IL-12 and IL-12-related dimeric cytokines in infectious diseases. Med Microbiol Immunol 193:1–17
Kawamura K, Bahar R, Natsume W, Sakiyama S, Tagawa M (2002) Secretion of interleukin-10 from murine colon carcinoma cells suppresses systemic antitumor immunity and impairs protective immunity against tumors. Cancer Gene Ther 9:109–115
Cui G, Goll R, Olsen T, Steigen SE, Husebekk A, Vonen B, Florholmen J (2007) Reduced expression of microenvironmental Th1 cytokines accompanies adenomas-carcinomas sequence of colorectum. Cancer Immunol Immunother 56:985–995
Stanilov N, Miteva L, Mintchev N, Stanilova S (2009) High expression of Foxp3, IL-23p19 and surviving mRNA in colorectal carcinoma. Int J Colorectal Dis 24:151–157
Miteva L, Stanilov N, Deliysky T, Mintchev N, Stanilova S (2009) Association of polymorphisms in regulatory regions of interleukin-12p40 gene and cytokine serum level with colorectal cancer. Cancer Invest 27(9):924–931
O’Hara RJ, Greenman J, MacDonald AW et al (1998) Advanced colorectal cancer is associated with impared interleukin 12 and enhanced interleukin 10 production. Clin Cancer Res 4:1943–1948
Shibata M, Nezu T, Kanou H, Abe H, Takekawa M, Fukuzawa M (2002) Decreased production of interleukin-12 and type 2 immune responses are marked in cachectic patients with colorectal and gastric cancer. J Clin Gastroenterol 34:416–420
Lopez V, Adris S, Bravo A, Chernajovsky Y, Podhajer L (2005) IL-12 and IL-10 expression synergize to induce the immune-mediated eradication of established colon and mammary tumors and lung metastasis. J Immunol 175:5885–5894
Bennett BL, Sasaki DT, Murray BW, O’Leary EC, Sakata ST, Xu W, Leisten JC, Motiwata A, Pierce S, Satoh Y, Bhagwat SS, Manning AM, Anderson DW (2001) Sp600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. PNAS 98:13681–13686
Inoue Y, Nakayama Y, Minagawa N, Katsuki T, Nagashima N, Matsumoto K, Shibao K, Tsurudome Y, Hirata K, Nagata N, Itoh H (2005) Relationship between interleukin-12-expressing cells and antigen-presenting cells in patients with colorectal cancer. Anticancer Res 25:3541–3546
Stanilov N, Miteva L, Deliyski T, Jovchev J, Stanilova S (2010) Advanced colorectal cancer is associated with enhanced Interleukin-23 and Interleukin-10 serum level. LabMedicine 41:159–163
Dalerba P, Maccalli C, Casati C, Castelli C, Parmiani G (2003) Immunology and immunotherapy of colorectal cancer. Crit Rev Oncol Hematol 46:33–57
Lin W, Karin M (2007) A cytokine-mediated link between innate immunity, inflammation and cancer. J Clin Invest 117:1175–1183
Johnson C, Han YY, Nathan H, McCarra J, Alpini G, Meng F (2012) Interleukin-6 and its receptor, key players in hepatobiliary inflammation and cancer. Transl Gastrointest Cancer 1:58–70
Lo CH, Lee SC, Wu PY, Pan WY, Su J, Cheng CW, Roffler SR, Chiang BL, Lee CN, Wu CW, Tao MH (2003) Antitumor and antimetastatic activity of IL-23. J Immunol 171:600–607
Shan B, Hao J, Li Q, Tagawa M (2006) Antitumor activity and immune enhancement of murine interleukin-23 expressed in murine colon carcinoma cells. Cell Mol Immunol 3:47–52
Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, Basham B, McClanahan T, Kastelein RA, Oft M (2006) IL-23 promotes tumor incidence and growth. Nature 442:461–465
Lan F, Zhang L, Wu J, Zhang J, Zhang S, Li K, Qi Y, Lin P (2011) IL-23/IL-23R: potential mediator of intestinal tumor progression from adenomatous polyps to colorectal carcinoma. Int J Colorectal Dis 26:1511–1518
Xu M, Mizoguchi I, Morishima N, Chiba Y, Mizuguchi J, Yoshimoto T (2010) Regulation of antitumor immune responses by the IL-12 family cytokines, IL-12, IL-23, and IL-27. Clin Dev Immunol. doi:10.1155/2010/832454
Utsugi M, Dobashi K, Ishizuka T, Endou K, Hamuro J, Murata Y, Nakazava T, Mori M (2003) c-Jun N-terminal kinase negatively regulates lipopolysaccharide-induced IL-12 production in human macrophages: role of mitogen-activated protein kinase in glutathione redox regulation of IL-12 production. J Immunol 171:628–635
Ma W, Gee K, Lim W, Chambers K, Angel JB, Kozlowski M, Kumar A (2004) Dexamethasone inhibits IL-12p40 production in lipopolysaccharide-stimulated human monocytic cells by down-regulating the activity of c-Jun N-terminal kinase, the Activation protein-1 and NF-κB transcription factors. J Immunol 172:318–330
Stadheim TA, Kucera GL (2002) c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for mitoxantrone- and anisomycininduced apoptosis in HL-60 cells. Leuk Res 26:55–65
Soh J-W, Mao Y, Kim M-G et al (2000) Cyclic GMP mediates apoptosis induced by sulindac derivatives via activation of c-jun NH2-terminal kinase 1. Clin Cancer Res 6:4136–4141
Rice PL, Peters SL, Beard KS, Ahnen DJ (2006) Sulindac independently modulates extracellular signal-regulated kinase 1/2 and cyclic GMP-dependent protein kinase signaling pathways. Mol Cancer Ther 5:746–754
Collett GP, Campbell FC (2004) Curcumin induces c-jun N-terminal kinase-dependent apoptosis in HCT116 human colon cancer cells. Carcinogenesis 25:2183–2189
Dobreva Z, Stanilova S, Miteva L (2008) Differences in the inducible gene expression and protein production of IL-12p40, Il-12p70 and IL-23: involvement of p38 and JNK kinase pathways. Cytokine 43:76–82
Acknowledgments
This work was supported by Grant No: 7/2010 from the Fund for Scientific and Mobile project from Faculty of Medicine at the Trakia University, Stara Zagora, Bulgaria.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Stanilov, N.S., Miteva, L.D., Dobreva, Z.G. et al. Monocytes expression of IL-12 related and IL-10 genes in association with development of colorectal cancer. Mol Biol Rep 39, 10895–10902 (2012). https://doi.org/10.1007/s11033-012-1987-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-012-1987-z