Antisecretory factor expression is regulated by inflammatory mediators and influences the severity of experimental autoimmune encephalomyelitis

Abstract

Antisecretory factor (ASF) was originally identified as a potent inhibitor of intestinal fluid secretion induced by a number of enterotoxins. In addition to its involvement in intestinal fluid secretion, ASF modulates the proliferation of memory/effector T cells and is expressed by cells of the immune system. This report describes the role of ASF in modulating immune responses and assesses the regulation of ASF during an in vivo immunological reaction. ASF expression was redistributed during adoptively transferred experimental autoimmune encephalomyelitis (EAE), and in response to other inflammatory stimuli. Administration of the anti-ASF antibody TLD-1A8A increased the clinical severity and duration of the disease. Consistent with these findings, addition of TLD-1A8A to T cell proliferation assays resulted in up-regulation of the proinflammatory cytokines IL-18 and IL-6 and in down-regulation of IL-10. Furthermore, we identified cytokines that regulated the expression of ASF at both the mRNA and protein level. ASF, therefore, appears to play a previously unappreciated and potentially important role in the regulation of immune responses.

Antisecretory factor as a potential health-promoting molecule in man and animals

“…In inflamed spinal cords, the mRNA expression showed a particular kinetics, with a drop at the onset of the clinical symptoms, a peak in coincidence with the highest disease severity and a decrease to baseline levels in correspondence with the complete recovery of the rats (28) . Despite the accumulation of AF-positive leucocytes in the CNS during the course of the disease, no overt changes were apparent in either expression levels or distribution of AF in peripheral organs, such as the spleen and lymph nodes.…”

“…The immunological stimulus, due to experimentally induced autoimmune encephalomyelitis in rats, modified the AF expression level and distribution in the inflamed nervous system, where the expression was enhanced in parenchymal microglia and infiltrating macrophages (28) . In inflamed spinal cords, the mRNA expression showed a particular kinetics, with a drop at the onset of the clinical symptoms, a peak in coincidence with the highest disease severity and a decrease to baseline levels in correspondence with the complete recovery of the rats (28) .…”

“…In the CNS, AF was found in blood vessels and perivascular cells, a bone marrow-derived cell population with immunoregulatory activity (8,29) . Davidson & Hickey (28) observed that macrophages expressed AF even in absence of a direct immunological stimulus, even if the activation of T cells induced an up-regulation of AF expression in macrophages.…”

“…Despite the accumulation of AF-positive leucocytes in the CNS during the course of the disease, no overt changes were apparent in either expression levels or distribution of AF in peripheral organs, such as the spleen and lymph nodes. Since AF levels are at almost undetectable levels on circulating monocytes, Davidson & Hickey (28) suggested a mechanism whereby AF is up-regulated on these cells at the area of inflammation upon macrophage activation and/or as a result of interaction with activated T lymphocytes. Pro-inflammatory factors, such as lipopolysaccharide (LPS) and interferon-g, up-regulated AF expression in rat alveolar macrophages only 72 -96 h after the treatment.…”

“…However, the effects on the immunological response observed in vitro did not clarify the nature of the interaction between AF and its antibody. Davidson & Hickey (28) hypothesised the existence of a receptor for AF on the surface of T cells which might be disrupted by the antibody, blocking the normal suppressing signal. Alternatively, the binding of T cell membrane-associated AF to the antibody might activate the antigen-presenting cells determining T cell proliferation (8) .…”