Immunomodulatory Effect of Vitamin C on Intracytoplasmic Cytokine Production in Neonatal Cord Blood Cells

Abstract

Background: Vitamin C (ascorbic acid) is an essential water-soluble antioxidant in cells and plasma. Besides metabolic functions, vitamin C is also known to contribute to immune homeostasis. Recently, it has been demonstrated that vitamin C has an inhibitory effect on the expression of pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) in adult whole blood cells in vitro. It has been postulated that vitamin C might be an interesting compound for modulation of an over-exuberant immune response, e.g., in patient cohorts susceptible for the development of systemic inflammatory response syndrome such as neonates. It was the aim of this study to investigate the modulatory effects of vitamin C on the production of inflammatory mediators in neonatal cord blood cells. Methods: The intracytoplasmic production of pro-inflammatory cytokines in neonatal cord blood cells stimulated with lipopolysaccharide or phorbol 12-myristate 13-acetate/ionomycin was assessed by flow-cytometry. Results: In contrast to our previous observations from adult whole blood cells, 20 mM vitamin C mildly stimulated the percentage of neonatal monocytes producing IL-6 after lipopolysaccharide stimulation (e.g., 11.3% increase compared to control, p = 0.005). In the presence of 20 mM vitamin C, even a stronger stimulatory effect was noted for the percentage of IL-8 (e.g., 46.7% increase, p < 0.001) and TNF-α producing neonatal monocytes (e.g., 69.2% increase, p = 0.004; n = 20). In accordance with adult data, the percentage of neonatal lymphocytes producing IL-2 after phorbol 12-myristate 13-acetate/ionomycin stimulation was dose-dependently reduced (e.g., 41.3% inhibition, p = 0.001, 20 mM vitamin C), while the percentage of TNF-α producing lymphocytes was mildly stimulated (e.g., 20.8% increase, p = 0.003, 20 mM vitamin C). Conclusions: Interestingly, vitamin C was demonstrated to enhance pro-inflammatory responses in CD14⁺ cord blood cells while only intracellular IL-2 production in CD3⁺ cells was diminished. These data suggest that vitamin C differentially influences intracytoplasmic cytokine production in adults and neonates, and further studies are needed to elucidate the underlying mechanisms of this selective immunomodulation.

Gene expression response to ascorbic acid in mice implanted with sarcoma S180 cells

“…Ascorbate plays a role in limiting inflammation, regulating cytokine production, and boosting the immune system [2][3][4][5][6][7][8]. It has a variety of properties that have generated interest in using it against cancer [9][10][11][12][13]: it enhances natural killer cell activity [14,15], increases collagen synthesis [16], inhibits capillary tubule formation (angiogenesis) [17,18], reduces inflammation in cancer patients [3], at millimolar concentrations, shows cytotoxicity against cancer cells [19][20][21][22][23][24] and the ability to reduce tumor growth in vivo [25][26][27][28][29][30][31][32][33][34].…”

Vitamin C Up-regulates Expression of CD80, CD86 and MHC Class II on Dendritic Cell Line, DC-1 Via the Activation of p38 MAPK

“…Vitamin C is regarded as an essential nutrient for the host defense mechanisms through the maintenance of immune homeostasis (1,2). High concentration of vitamin C is accumulated in most immune cells including, neutrophils, macrophages, B cells and T cells, and it is rapidly decreased by infection or stress (3-6).…”

Thalidomide has anti-inflammatory properties in neonatal immune cells

“…Vitamin C behaved similarly in apoptosis assays providing the basis for future studies. 2 Interestingly, inhibition of CD34+ stem cells by lenalidomide upon up-regulation of a negative regulator of cell cycle has already been demonstrated. 55 Although providing opportunities for prolonged inflammation by supporting survival of all leukocytes, thalidomide's anti-apoptotic impact on neonatal cells could improve lymphocyte death in neonatal SIRS and circumvent lymphopenia.…”

“…10,11 Therefore, recent investigations aim to find immunomodulatory drugs which may prevent or beneficially influence SIRS at innate and adaptive stages of immune responses in neonates at risk. 2,12 Thalidomide is a structurally altered barbiturate, known as Contergan since the 1950s, which caused limb defects in offspring. It was re-introduced in 1997 for the treatment of erythema nodosum leprosum, chronic autoimmune diseases, multiple myeloma and, finally, solid neoplasms.…”