Increased transforming growth factor‐β, interleukin‐4, and interferon‐γ in multiple sclerosis

Abstract

The inflammatory nature of multiple sclerosis (MS) implicates the participation of immunoregulatory cytokines, including the T-helper type 1 (Th1) cell-associated interferon-gamma (IFN-gamma), the Th2 cell-related interleukin-4 (IL-4), and the immune response-downregulating cytokine transforming growth factor-beta (TGF-beta), but proof for their involvement in MS has been lacking. By adopting in situ hybridization with complementary DNA oligonucleotide probes for human IFN-gamma IL-4, and TGF-beta, the expression of mRNA for these cytokines was detected in mononuclear cells (MNC) from blood and cerebrospinal fluids. Strongly elevated levels of MNC expressing all three cytokines were found in peripheral blood and at even higher frequencies in cerebrospinal fluid from untreated patients with MS and optic neuritis, i.e., a common first manifestation of MS, compared with patients with other neurological diseases and healthy subjects. In MS and optic neuritis, IL-4 mRNA expressing cells predominated, followed by TGF-beta- and IFN-gamma-positive cells. Control patients with myasthenia gravis had similarly elevated levels of IFN-gamma and TGF-beta and TGF-beta mRNA expressing blood MNC but lower numbers of IL-4-positive cells. No or slight disability of MS was associated with high levels of TGF-beta mRNA expressing cells, while MS patients with moderate or severe disability had high levels of IFN-gamma-positive cells. IFN-gamma and TGF-beta may have opposing effects in MS, and treatments inhibiting IFN-gamma and/or promoting TGF-beta might ameliorate MS.

T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis

“…The IL-4 production by T cells from the HRs accords with the finding of high numbers of IL-4-producing cells in blood and cerebrospinal fluid of patients with MS, 42 and with the increases in the levels of messenger RNA for IL-4 (along with IL-2, IL-4, IL-6, IFN-c and IL-1a) in spinal cord samples from mice during the acute phase of EAE. 43 By contrast, a decrease in the IL-4 production by proteolipid protein-stimulated T-cell clones from patients with MS during acute attacks has also been reported.…”

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

“…However, in a neurodegenerative disease model, transgenic overexpression of TGF-b1 in astrocytes exacerbates the disease pathology (WyssCoray et al 1997). In patients with multiple sclerosis, high levels of TGF-b1 mRNA expression in mononuclear peripheral cells have been associated with reduced disability, disease duration, and disease brain activity (Link et al 1994;Söderström et al 1995;Bertolotto et al 1999), although clinical trials of TGF-b treatment of patients with multiple sclerosis were terminated because of non-neurological toxicity (Wiendl et al 2000).…”

Betulinic acid regulates generation of neuroinflammatory mediators responsible for tissue destruction in multiple sclerosis in vitro

“…Regarding MS, it has been shown that IL-17 is elevated in immune cells within the CNS and at the periphery and that it contributes to the pathogenesis of the disease, eg through distortion of the blood-brain-barrier [19][20][21] . It has also been shown that IFN-γ-producing cells are present within the CNS and at the periphery of MS patients [22] , and that treatment of MS patients with IFN-γ exacerbates the disease [23] . Therefore, inhibiting IL-17 and IFN-γ generation is relevant when modulating the EAE course and also has relevance when evaluating therapeutic efficiency in MS.…”