Il-27 shares structural similiarities with IL-6,IL-12 and IL-23, all of wich play important roles in the biology of helper T cells and have established roles in oncogenesis and tumor progression.
Il-27 is widely regarded as an immunosoppresive cytokine as it can stimulate the secretion of Il-10 and directly suppress the differentiation of TH2 and TH17.
It has also been shown to soppress the differentiation of FOXP3 and to promote TH1 immune responce thereby exerting pro-infiammatory effects in some circumstances.
Despite this , multiple groups have shown that Il-27 exerts antineoplastic effects through various mechanisms, including CD8+T and natural killer T cell activation, IFN production, antibody- dependent cellular cytotoxicity, antiangiogenesis, direct suppression of tumor growth and cyclooxygenase-2 inhibition.Unfortunately the use of cytokines is burdend by a series of side effects: cardiovascular compliations, largely caused by a syndrome of hyperpermeability and all organs can be effected by other toxicity effects especially the kidneys, liver, lungs, nervous system and the skin but often are reversible and Il-27 would seem to have a lower toxicity than other interleukins.
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Following are some examples of what is said.
Interleukin -27 inhibits pediatric B-acute lymphoblastic leukemia.
A group of researchers at the 'Istituto Giannina Gaslini Institute of Genoa, coordinated by Irma Airoldi, head of the Laboratory Immunology and Cancer funded by the Italian Association for Cancer Research (AIRC), has discovered that a protein called interleukin-27 is a potent anti--tumoral agent in acute lymphoblastic leukemia of children.
B-acute lymphoblastic leukemia represents the most common pediatric hematological tumor that derives from the aberrant proliferation of early B lymphocytes in the bone marrow. Although most of the B-ALL children take advantage from current therapeutic protocols, some patients relapse and need alternative therapies. B-ALL cells from pediatric patients injected intravenously into
NOD/SCID/Il2rg−/− (NSG) mice gave rise to leukemic spreading that was severely hampered by IL-27; IL-27-treated mice, compared with controls, showed
significant reduction of putative B-ALL-initiating cells and blasts in the peripheral blood , bone marrow and spleen.
Mice were sacrificed 10 to 12 weeks later when signs of poor health became evident in controls. Cells of peripheral blood cells, spleen and bone marrow from each animal were collected and subjected to immunophenotypic evaluation and flow cytometric analysis.
Notably, IL-27 significantly reduced the presence of human CD45+CD33+ leukemia cells in peripheral blood (P < 0.0001), bone marrow (P = 0.0015), and spleen (P < 0.0001) as compared with control.
Morphologic and immunohistochemical analyses of spleens collected from controls (n = 5) and IL-27–treated mice (n = 5) revealed that human acute myelocytic leukemia(AML) cells gave rise to multiple and wide neoplastic infiltrates. These infiltrates were supplied with a well-developed microvascularization and sustained by a rich stromal reticulin fiber network that seemed to be shaped to intratumoral microvascularization .By contrast, the spleen of IL-27–treated mice showed smaller and less frequent neoplastic infiltrates and an almost absent microvascularization and reticulin fiber support, as revealed by both laminin staining and silver impregnation.
AML cells infiltrating the spleens from IL-27–treated mice showed downregulation of different proangiogenic genes includingangiopoietin ANGPT)2 and 3, CXCL6 and VEGF-C ,as well as genes involved in the dissemination/spreading process such as CXCR4(CXCR4 represents the receptor for CXCL12 which was found to be implicated in the growth and dissemination of solid and hematologic tumors) and matrix metalloproteinase (MMP)7. However, it is of note that IL-27 also induced upregulation of the angiostatic molecule tissue inhibitor of metalloproteinase (TIMP)2, indicating that IL-27–mediated inhibition of angiogenesis may result from the regulation of both proangiogenic as well as angiostatic factors.
Reduction of the CXCR4+ leukemic cells by IL-27 treatment in vivo.
Interleukin-27 inhibits the growth of pediatric acute myeloid leukemia in NOD/SCID/Il2rg-/- mice, 2012
IL-27 Directly Restrains Lung Tumorigenicity by Suppressing Cyclooxygenase-2-Mediated Activities
Gene transfer of IL-27 to tumor cells has been proven to inhibit tumor growth in vivo by antiproliferation, antiangiogenesis, and stimulation of immunoprotection. Mice inoculated with LLC/scIL-27 displayed retardation of tumor growth. Production of IL-12, IFN-γ, and cytotoxic T cell activity against LLC-1 was manifest in LLC/scIL-27-injected mice. On the cellular level, the LLC/scIL-27 transfectants had reduced malignancy, including down-regulation of vimentin expression and reduction of cellular migration and invasion. The suppression of tumorigenesis by IL-27 on lung cancer cells was further confirmed by the treatment with rIL-27 on the murine LLC-1 and human non-small cell lung carcinoma (NSCLC) cell lines. PGE2-induced vimentin expression,movement, and invasiveness were also suppressed by the treatment with rIL-27. IL-27 not only suppresses expression of COX-2 and PGE2 but also decreases the levels of vimentin and the abilities of cellular migration and invasion. Furthermore, inoculation of LLC/scIL-27 into immunodeficient NOD/SCID mice also exhibited reduced tumor growth.
IL-27 Directly Restrains Lung Tumorigenicity by Suppressing Cyclooxygenase-2-Mediated Activities,2014
Il-27 inhibits human PCa cell proliferation in vitro
To assess the ability of IL-27 to affect prostate cancer cell proliferation and apoptosis, cells were cultured with or without human recombinant (hr) IL-27 for 120 hours and an aliquot of these cells was harvested every 24 hours for flow cytometry with CFSE intracellular staining, cell count or annexin V/PI staining.
IL-27 inhibited PC3 cell proliferation after 120 hours as shown by the higher CFSE intensity in IL-27 treated cells at this time point. A similar behavior was observed in DU145.
PC3 or DU145 cells were injected subcutaneously in athymic nude mice that were subsequently treated with IL-27.
L-27 significantly decreased their proliferation , as shown by Ki-67 immunostaining and induced multiple foci of ischemic necrosis, as assessed by histology, in association with a defective microvascular supply, as shown by CD31 immunostaining.
Inhibition of human PC3 and DU145 cell growth in vivo by IL-27 treatment.
IL-27 significantly down-regulated, in both cell lines, pro-angiogenic genes such as vascular endothelial growth factor receptor (VEGFR)1/FLT1, fibroblast growth factor receptor 3 and prostaglandin G/H synthase 1 .
IL-27 down-regulated mRNA expression of insulin-like growth factor (IGF)1, matrix metalloproteinase (MMP)2 , tumor necrosis factor (TNF) alphaand cyclooxygenase (COX) -1 .
The antitumor potential of Interleukin-27 in prostate cancer, 2013
Conclusion
Based on the positive results in some type of cancers it is hoped that new trials will be realized in order to explore the toxicity and the possibility of reducing it by changing the route of administration and dosage
It is hoped that these findings have early important effects in the therapeutic treatment of our patients.
