Exogenous Melatonin Up-Regulates Expression of CD62L by Lymphocytes in Aged Mice under Inflammatory and Non-Inflammatory Conditions.

It is well documented that age-related impaired functioning of immunocompetent cells is associated with an increase in the rates of chronic inflammatory diseases. Recently, an ability of melatonin to modulate inflammatory processes by regulating leucocyte recruitment has been demonstrated. However, to date, no studies have attempted to determine the impact of melatonin on the expression of CD62L by lymphocytes. CD62L, also known as L-selectin, is required for the entry of lymphocytes into secondary lymphoid organs, sites of tumor growth and chronic inflammation through high endothelial venules. Here, we investigated the effect of melatonin at physiological concentrations on the expression of CD62L by T and NK cells in vivo and in vitro. We demonstrated that NK and CD3+ T cells obtained from the spleen of aged mice were characterized by decreased expression of CD62L compared to young mice. Melatonin administration up-regulated the levels of surface CD62L on NK and T cell populations in aged mice under non-inflammatory conditions and on CD8+ T cells in aged mice with chronic inflammation. Pre-incubation with melatonin prevented the reduction in CD62L expression by CD8+ T cells induced by the co-cultivation of peripheral blood mononuclear cells with human pancreatic adenocarcinoma cell line (MiaPaCa-2). The obtained results suggest that melatonin can modulate lymphocyte homing into lymph nodes and sites of chronic inflammation and, therefore, can stimulate immune responses in chronic inflammatory conditions associated with aging.

Chronic Inflammation Contributes to Tumor Growth: Possible Role of L-Selectin-Expressing Myeloid-Derived Suppressor Cells (MDSCs).

Recent data have demonstrated that chronic inflammation is a crucial component of tumor initiation and progression. We previously reported that immature myeloid-derived suppressor cells (MDSCs) with immunosuppressive activity toward effector T cells were expanded in experimental chronic inflammation. We hypothesized that elevated levels of MDSCs, induced by chronic inflammation, may contribute to the progression of tumor growth. Using the Ehrlich carcinoma animal model, we found increased tumor growth in mice with chronic adjuvant arthritis, which was accompanied by a persistent increase in the proportion of splenic monocytic and granulocytic MDSCs expressing CD62L (L-selectin), when compared to tumor mice without adjuvant arthritis. Depletion of inflammation-induced MDSCs resulted in decreased tumor growth. In vitro studies demonstrated that increased expression of CD62L by MDSCs was mediated by TNFα, elevated concentrations of which were found in tumor mice subjected to chronic inflammation. Moreover, the addition of exogenous TNFα markedly enhanced the suppressive activity of bone marrow-derived MDSCs, as revealed by the ability to impair the proliferation of CD8+ T cells in vitro. This study provides evidence that chronic inflammation may promote tumor growth via induction of CD62L expression by MDSCs that can facilitate their migration to tumor and lymph nodes and modulation of their suppressor activity.

Expansion of CD11b+Ly6Ghigh and CD11b+CD49d+ myeloid cells with suppressive potential in mice with chronic inflammation and light-at-night-induced circadian disruption.

OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) are important negative regulators of immune processes in cancer and other pathological conditions. We suggested that MDSCs play a key role in pathogenesis of chronic inflammation, which precedes and, to a certain extent, induces carcinogenesis. The present study aimed at investigation of MDSCs arising during chronic inflammation and light-at-night (LN)-induced stress, which is shown to accelerate chronic diseases. SUBJECTS: 67 CD-1 mice and in vitro MDSC cultures. TREATMENT: Adjuvant arthritis was induced by a subdermal injection of complete Freund's adjuvant. LN was induced by illumination of 750 lx at night. METHODS: Flow cytometry for evaluation of cell phenotypes and MTT standard test for cell proliferation were used. RESULTS: Increased levels of splenic CD11b+Ly6Ghigh and CD11b+CD49d+ myeloid cells possessing suppressive potential in mice with adjuvant arthritis are shown. LN amplifies the process of CD11b+Ly6Ghigh expansion in mice with adjuvant arthritis. Expression of CD62L and CD195 is elevated on the myeloid cells during exposure to LN. CONCLUSIONS: Our study raises the possibility that CD11b+Ly6Ghigh and CD11b+CD49d+ MDSCs play an important role in the induction of immunosuppressive environment typical for chronic inflammation. Also, LN can affect immune responses during chronic inflammation through recruitment of MDSCs from the bone marrow.