The significance of an increase in soluble interleukin-2 receptor level in colorectal cancer and its biological regulating role in the physiological switching of the immune response cytokine network from TH1 to TH2 and back

Abstract

Current research has still not clarified the biological role of soluble interleukin(IL)-2 receptor (sIL-2R) and the significance of its increase in the serum of colon cancer patients compared to healthy subjects. To address these questions at the immunological level in a group of patients and healthy subjects, we determined the sIL-2R level in the serum and its release from peripheral blood mononuclear cells (PBMC) as a function of tumour necrosis factor (TNF) alpha, IL-1 alpha, IL-1 beta, IL-2, interferon (IFN) gamma, IL-4, IL-6 and IL-10 levels in the serum and PBMC production; and PBMC proliferative responses to IL-2, IL-4 and anti-CD3 monoclonal antibody (CD3), variously combined. The level of sIL-2R in patients' serum was higher than in healthy subjects and correlated with the stage of advancement. Moreover, while in healthy subjects the serum level of sIL-2R was not significantly correlated with other parameters, in patients it was positively related to IL-4, IL-6 and IL-10 serum levels, PBMC IL-4 production and to the PBMC proliferative response to CD3 and CD3 + IL-2; it was negatively correlated to IL-2 serum level and IL-1 beta PBMC release. A negative connection between IFN gamma serum level and the PBMC production of sIL-2R was also found. This suggests that the increase of sIL-2R in the serum of patients, compared to healthy subjects, is involved in the inappropriate expansion of the T helper (TH2) suppressive immune response, which we previously reported. The multivariate statistical method supported the above suggestions and we also found that, in healthy subjects, the up- and down-regulation of sIL-2R in the serum within the physiological ranges seems to have a regulating role in the relationships between TNF alpha, IFN gamma and IL-4, IL-6, contributing to the operation of the cytokine network between TH1 and TH2 cells. However, in patients compared to healthy subjects the increased sIL-2R serum level seems to direct the immune response towards a suppressive type, which may be due to an alteration in the above-mentioned physiological regulating role.

Endogenous Interleukin-4 Promotes Tumor Development by Increasing Tumor Cell Resistance to Apoptosis

“…The increased IL-4 level in tumor sites and the augmented IL-4-producing activity of immune cells have been observed in cancer patients (1)(2)(3)(4)(5)27). To test whether IL-4 influences tumor growth in vivo, we examined the growth of MCA205 fibrosarcoma in syngeneic mice treated with 11B11, an IL-4-neutralizing antibody, or control, an isotype-matched antibody.…”

Sarcoidosis: immunopathogenetic concepts and their clinical application

“…However, immunosuppressive functions via competition for cytokines or pro-inflammatory functions via prolongation of the cytokine half-life are conceivable. Recent studies indicate a role for sIL-2R in the regulation of Th1/Th2 responses [231] and an antifibrotic capability of sTNF-R [232]. An anti-inflammatory role for the IL-1 receptor antagonist (IL-1RA), an immune-regulatory molecule found in BAL fluid and granulomatous lesions of sarcoidosis patients [190,233,234], was established in animal models [235].…”

Effect of nutrient starvation on proliferation and cytokine secretion of peripheral blood lymphocytes

“…Th1/Th2 imbalance has been reported to be associated with various diseases. For example, Th1 predominance is reported in rheumatoid arthritis (16), whereas Th2 predominance is reported in certain neoplastic diseases, including basal cell carcinoma (17,18), multiple myeloma (19), and colon cancer (20,21). However, the mechanisms underlying these imbalances remain to be elucidated.…”