The potential impact of sickness-motivated behavior on the expression of neuropsychiatric disturbances in systemic lupus erythematosus.

Activation of the peripheral immune system is often accompanied by changes in cognition, ingestive behavior, sleep pattern, and sexual drive; collectively referred to as sickness behavior. Mounting evidence suggests that sickness behavior may be a purposeful attempt on the part of an organism to conserve energy and thereby facilitate recuperation. Illnesses characterized by chronic, uncontrolled immune reactivity such as systemic lupus erythematosus are also frequently associated with impaired emotionality and cognition; which, unlike sickness behavior, are conventionally thought to emanate from fixed structural lesions of the brain. Clinical observations, however, indicate that the neuropsychiatric disturbances in lupus may wax and wane in intensity and suggest the hypothesis that sickness-motivated behavior may significantly influence the neuropsychiatric manifestations of systemic lupus erythematosus and, perhaps, those of other autoimmune diseases associated with neuroinflammation. The hypothesis that patients with systemic lupus erythematosus undergo a reorganization of their motivational priorities, which influences cognitive performance and emotional output, may be examined using validated behavior paradigms in autoimmune MRL-MpJ-Tnfrsf6(lpr) (MRL-lpr/lpr) mice that spontaneously develop a lupus-like illness accompanied by disturbances in cognition and emotionality. Confirming that sickness-motivated behavior contributes to the aberrations in cognition and emotionality exhibited by an experimental model of systemic lupus erythematosus might have important therapeutic and prognostic implications by invoking the possibility that similar motivational effects may be influencing cognitive and/or emotional output in patients with neuropsychiatric lupus.

Astrocyte production of the chemokine macrophage inflammatory protein-2 is inhibited by the spice principle curcumin at the level of gene transcription.

BACKGROUND: In neuropathological processes associated with neutrophilic infiltrates, such as experimental allergic encephalitis and traumatic injury of the brain, the CXC chemokine, macrophage inflammatory protein-2 (MIP-2) is thought to play a pivotal role in the induction and perpetuation of inflammation in the central nervous system (CNS). The origin of MIP-2 in inflammatory disorders of the brain has not been fully defined but astrocytes appear to be a dominant source of this chemokine.Curcumin is a spice principle in, and constitutes approximately 4 percent of, turmeric. Curcumin's immunomodulating and antioxidant activities suggest that it might be a useful adjunct in the treatment of neurodegenerative illnesses characterized by inflammation. Relatively unexplored, but relevant to its potential therapeutic efficacy in neuroinflammatory syndromes is the effect of curcumin on chemokine production. To examine the possibility that curcumin may influence CNS inflammation by mechanisms distinct from its known anti-oxidant activities, we studied the effect of this spice principle on the synthesis of MIP-2 by astrocytes. METHODS: Primary astrocytes were prepared from neonatal brains of CBA/CaJ mice. The cells were stimulated with lipopolysaccharide in the presence or absence of various amount of curcumin or epigallocatechin gallate. MIP-2 mRNA was analyzed using semi-quantitative PCR and MIP-2 protein production in the culture supernatants was quantified by ELISA. Astrocytes were transfected with a MIP-2 promoter construct, pGL3-MIP-2, and stimulated with lipopolysaccharide in the presence or absence of curcumin. RESULTS: The induction of MIP-2 gene expression and the production of MIP-2 protein were inhibited by curcumin. Curcumin also inhibited lipopolysaccharide-induced transcription of the MIP-2 promoter reporter gene construct in primary astrocytes. However MIP-2 gene induction by lipopolysaccharide was not inhibited by another anti-oxidant, epigallocatechin gallate. CONCLUSION: Our results indicate that curcumin potently inhibits MIP-2 production at the level of gene transcription and offer further support for its potential use in the treatment of inflammatory conditions of the CNS.

Proinflammatory cytokine genes are constitutively overexpressed in the heart in experimental systemic lupus erythematosus: a brief communication.

The heart is one of a number of organs that may be affected in systemic lupus erythematosus (SLE), a prototypic autoimmune disease. Potential anatomical sites of involvement include the myocardium, pericardium, endocardium, valves, conduction system and blood vessels that subserve the heart. Typically, the severity of cardiovascular disease in lupus correlates with the degree of systemic inflammation, which is mirrored by the level of C-reactive protein (CRP) in the plasma. C-reactive protein, in turn is regulated by proinflammatory cytokines, such as interleukins (ILs) 1beta and 6. These cytokines have been found in functionally and/or structurally damaged areas of the heart and have been implicated in disease pathogenesis. It has been assumed that the source of these putatively pathogenetically relevant cytokines in the compromised heart is infiltrating mononuclear cells. This study tests the hypothesis that cardiomyocytes per se may contribute to proinflammatory cytokine production in the setting of systemic inflammation. Using as the experimental model MRL/MpJ-Tnfrs6(lpr) (MRL-lpr/lpr) mice, which spontaneously manifest an autoimmune syndrome that has clinical features of SLE, we show that ventricular homogenates and ventricular cardiomyocytes constitutively overexpress genes encoding the proinflammatory cytokines IL-1beta, IL-6, IL-10, and gamma interferon. The results suggest the possibility that proinflammatory cytokines emanating from the heart may actually contribute to the high levels of CRP that appear to aid in predicting subsequent cardiac events. Viewed in this setting, CRP becomes a footprint of an ongoing pathogenic process mediated, in part, by the heart muscle itself.

The potential pathogenetic link between peripheral immune activation and the central innate immune response in neuropsychiatric systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. Neuropsychiatric disturbances unexplained by drugs or by other untoward manifestations of disease are present in up to one-half of SLE patients and have profound economic and social impact. In patients with neuropsychiatric SLE, structural lesions have been identified in the hippocampus and proinflammatory cytokines have been detected in the cerebrospinal fluid. Similarly, murine models of lupus, such as MRL-lpr/lpr mice display behavioral disturbances which map to the hippocampus and exhibit overexpression of proinflammatory cytokine genes in hippocampal homogenates. Neuropsychiatric SLE typically occurs in the presence of serologically and clinically active lupus. In animal models of SLE, such as MRL-lpr/lpr, NZB, BXSB, and [NZB x NZW]F(1), uncontrolled autoreactivity in the periphery is accompanied by behavioral disturbances that are chronic and progressive. These observations suggest the hypothesis that central nervous system disease in SLE is driven by cross-talk between the peripheral immune system and the brain's innate immune system, which results in the inexorable activation of astrocytes, microglia, and/or neurons within the hippocampus. This leads to overproduction of brain cytokines, which induce the synthesis of pro-oxidant molecules, such as eicosanoids and reactive oxygen species, with resultant tissue injury. The cascade becomes self-perpetuating and eventuates in neuronal death, which is followed by impaired cognition. A better understanding of the molecular events that operate in the pathogenesis of neuropsychiatric SLE may provide the basis for a more rational therapeutic approach to this incompletely understood disease.

Arachidonoyl-phospholipid remodeling in proliferating murine T cells.

BACKGROUND: Previous studies have shown that the functional capacity of T cells may be modulated by the composition of fatty acids within, and the release of fatty acids from membrane phospholipids, particularly containing arachidonic acid (AA). The remodeling of AA within membrane phospholipids of resting and proliferating CD4+ and CD8+ T cells is examined in this study. RESULTS: Splenic T cells were cultured in the presence or absence of anti-CD3 mAb for 48 h then labeled with [3H]AA for 20 min. In unstimulated cells, labeled AA was preferentially incorporated into the phosphoglycerides, phosphatidylcholine (PC) followed by phosphatidylinositol (PI) and phosphatidylethanolamine (PE). During a subsequent chase in unlabeled medium unstimulated CD4+ and CD8+ T cells demonstrated a significant and highly selective transfer of free, labeled AA into the PC pool. In contrast, proliferating CD4+ and CD8+ T cells distributed labeled [3H]AA predominantly into PI followed by PC and PE. Following a chase in AA-free medium, a decline in the content of [3H]AA-PC was observed in association with a comparable increase in [3H]AA-PE. Subsequent studies revealed that the cold AA content of all PE species was increased in proliferating T cells compared with that in non-cycling cells, but that enrichment in AA was observed only in the ether lipid fractions. Finally, proliferating T cells preincubated with [3H]AA exhibited a significant loss of labeled arachidonate in the PC fraction and an equivalent gain in labeled AA in 1-alk-1'-enyl-2-arachidonoyl-PE during a chase in unlabeled medium. CONCLUSION: This apparent unidirectional transfer of AA from PC to ether-containing PE suggests the existence of a CoA-independent transacylase system in T cells and supports the hypothesis that arachidonoyl phospholipid remodeling may play a role in the regulation of cellular proliferation.

Tea pigments inhibit the production of type 1 (T(H1)) and type 2 (T(H2)) helper T cell cytokines in CD4(+) T cells.

Tea pigments are oxidized products of polyphenols derived from tea leaves (Camellia sinensis). Theaflavins are constituents of tea pigments with antioxidant, antineoplastic and antiinflammatory properties similar to their parent compounds. The biological properties of polyphenols and theaflavins have been linked to their capacity to inhibit the activation of nuclear factor-kappaB (NF-kappaB), a transcription factor, which is critically involved in the molecular regulation of a number of proinflammatory cytokines. The current study examines the requirement for NF-kappaB in the immunosuppressive effects mediated by tea antioxidants. Specifically, we tested the hypothesis that cytokines produced by type 1 (T(H1)) CD4(+) T cells which require NF-kappaB for gene expression, such as interleukin-2 (IL-2) and interferon gamma (IFN gamma), are selectively inhibited by tea pigments. We found that tea pigments potently suppress IL-2 secretion, IL-2 gene expression and the activation of NF-kappaB in murine spleens enriched for CD4(+) T cells, as expected. Consistent with our hypothesis, tea pigments also inhibited the induction of IFNgamma mRNA. However, the expression of the T(H2) cytokines IL-4 and IL-5, which lack functional NF-kappaB sites within their promoters was unexpectedly suppressed by tea pigments, as well. The results indicate that NF-kappaB may be only one of multiple transcription factors inhibited by tea pigments.