Regulation of cytokine gene expression in experimental autoimmune encephalomyelitis

Abstract

We previously reported that recovery of Lewis rats from experimental autoimmune encephalomyelitis (EAE) is associated with the appearance of suppressor T cells (Ts). These Ts secrete TGF-beta which down-regulates the production of inflammatory cytokines by the effector T cells that mediate this disease. In the present study, we immunized Lewis rats with myelin basic protein (MBP)+CFA, and evaluated purified T cells and MBP-activated spleen cells (SpC) during the paralytic phase (day 12) and after recovery (days 30-33) for TGF-beta and interferon (IFN)-gamma mRNA. We used reverse transcriptase-polymerase chain reaction (RT-PCR), quantitated on the basis of beta-actin mRNA. Abundant IFN-gamma mRNA was present in MBP-activated SpC obtained on day 12. In contrast, only trace IFN-gamma mRNA was detected in day 30 activated SpC, and no IFN-gamma mRNA was present in purified, nonactivated T cells obtained at either time. The level of IFN-gamma mRNA correlated with secretion of IFN-gamma as determined by ELISA on SpC culture supernatants, and with severity of adoptively transferred EAE by the activated SpC. Thus, it appears that IFN-gamma mRNA is both transcribed and translated in response to antigen activation, resulting in secretion of IFN-gamma by the disease-inducing Te. In contrast, when we used RT-PCR to investigate the expression of TGF-beta mRNA, we found the transcript present in isolated T cells and MBP-activated SpC obtained from rats at both days 12 and 30. The presence of TGF-beta mRNA at time points corresponding to both clinical EAE and recovery suggests post-transcriptional regulation of the production of this immunoregulatory cytokine.

Inflammatory genes and neural activity: involvement of immune genes in synaptic function and behavior

“…The expression and function of pro-inflammatory cytokines in the brain such as interleukin-1 (IL-1) beta and tumor necrosis factor (TNF) alpha has been well documented in brain injury cases including ischemia, head trauma, infections and stroke (1,2,3,4). In addition, cytokines and chemokines have been shown to play a role in the pathogenesis and progression of autoimmune diseases such as multiple sclerosis and experimental allergic encephalomyelitis (5,6,7). Cytokine signaling to the brain and propagation within the brain parenchyma have also been shown to be important routes of immune to central nervous system feedback regulation (8,9,10,11,12,13,14,15).…”

Increased numbers of mononuclear cells from blood and CSF expressing interferon‐gamma mRNA in multiple sclerosis are from both the CD4+ and the CD8+ subsets

“…Apart from being an indicator of cellular activation, IFNγ may also exert direct effects in the development of MS lesions due to its pro‐inflammatory properties ( Farrar and Schreiber, 1993), its ability to worsen MS when systemically administered ( Panitch et al ., 1987 ), and its ability to kill oligodendrocytes in vitro ( Vartanian et al ., 1995 ; Baerwald and Popko, 1998) and in vivo ( Horwitz et al ., 1997 ). However, it should be noted that cellular IFNγ mRNA expression is not exclusively followed by IFNγ secretion, although this is generally the case ( Issazadeh et al ., 1995 ; Zitron et al ., 1996 ). The presence of elevated numbers of IFNγ mRNA expressing PBLs and CSF cells in not unique to MS, because it is apparent in other inflammatory CNS diseases ( Navikas et al ., 1995 ).…”

Concordance and contradiction concerning cytokines and chemokines in experimental demyelinating disease

“…Encephalitogenic MBP-specific T cells upregulate interferon-gamma (IFN-␥) mRNA (Zitron et al, 1996) and secrete large quantities of IFN-␥ in vitro (McDonald and Swanborg, 1988) when stimulated with antigen. This suggests that this cytokine is involved in the pathogenic process, a hypothesis consistent with the clinical report that patients with relapsing-remitting MS had exacerbations while undergoing treatment with IFN-␥ (Panitch et al, 1987).…”