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Review
, 84 (4), 900-14

Age-associated Changes in Immune and Inflammatory Responses: Impact of Vitamin E Intervention

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Review

Age-associated Changes in Immune and Inflammatory Responses: Impact of Vitamin E Intervention

Dayong Wu et al. J Leukoc Biol.

Abstract

Aging is associated with dysregulated immune and inflammatory responses. Declining T cell function is the most significant and best-characterized feature of immunosenescence. Intrinsic changes within T cells and extrinsic factors contribute to the age-associated decline in T cell function. T cell defect seen in aging involves multiple stages from early receptor activation events to clonal expansion. Among extrinsic factors, increased production of T cell-suppressive factor PGE(2) by macrophages (Mphi) is most recognized. Vitamin E reverses an age-associated defect in T cells, particularly naïve T cells. This effect of vitamin E is also reflected in a reduced rate of upper respiratory tract infection in the elderly and enhanced clearance of influenza infection in a rodent model. The T cell-enhancing effect of vitamin E is accomplished via its direct effect on T cells and indirectly by inhibiting PGE(2) production in Mphi. Up-regulated inflammation with aging has attracted increasing attention as a result of its implications in the pathogenesis of diseases. Increased PGE(2) production in old Mphi is a result of increased cyclooxygenase 2 (COX-2) expression, leading to higher COX enzyme activity, which in turn, is associated with the ceramide-induced up-regulation of NF-kappaB. Similar to Mphi, adipocytes from old mice have a higher expression of COX-2 as well as inflammatory cytokines IL-1beta, IL-6, and TNF-alpha, which might also be related to elevated levels of ceramide and NF-kappaB activation. This review will discuss the above age-related immune and inflammatory changes and the effect of vitamin E as nutritional intervention with a focus on the work conducted in our laboratory.

Figures

Fig. 1.
Fig. 1.
Immune synapse formation and intracellular signaling pathways involved in T cell activation. TCR engagement triggers the expansion and rearrangement of nascent T cell-APC contacts, leading to the formation of immune synapse. The image picture on the upper left shows an effective immune synapse in which ZAP70 (served as an example of signaling molecules) is redistributed. Activation of TCR and coligation of the CD4 activate Src family protein tyrosine kinase Lck, which mediates the phosphorylation of immunoreceptor tyrosine-based activation motifs on CD3-ζ. This leads to the recruitment and activation of ZAP70, which subsequently phosphorylates adaptor proteins, such as the linker for activated T cells (LAT), which in turn ligates phospholipase Cγ1 (PLCγ1) and Grb2-related adaptor downstream of Src homology collagen-like (Shc; Gads)/Sh2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76)/Vav to activate downstream signaling pathways, ultimately leading to the activation of different nuclear transcription factors necessary for cytokine gene transcription. The yellow boxes represent the molecules that are known to have reduced abundance and/or function with aging, and those in green represent the molecules that are known to be impaired by aging and restored by vitamin E. An age-associated change in Lck redistribution is observed by some [50] and not the other investigators [61]. The bar figure on the lower left presents the results from a study by Marko et al. [61], in which vitamin E supplementation significantly improved and restored the impaired redistribution of signaling molecules to the immune synapse in old T cells. *, A significant age difference; #, a significant vitamin E effect. The bar figure is reproduced with permission from Marko et al. [61].
Fig. 2.
Fig. 2.
Sphingolipid metabolism and ceramide synthesis. Ceramide lies in the center of the sphingolipid metabolism network. Ceramide can be generated via breakdown of sphingomyelin by SMase, including neutral, acid, and alkaline SMase, or synthesized de novo from the condensation of palmitate and serine under action of serine palmitoyl transferase (SPT). Metabolic interconversion between ceramide and other sphingolipids adds additional complexity to the study on ceramide, as it can be converted to other interconnected sphingolipids, and unique functions of these sphingolipids are increasingly recognized. Several compounds are known to affect the steps in ceramide synthesis pathways and thus, have been used to manipulate cellular ceramide levels in the study for identifying its role in a variety of biological processes. FB1, Fumonisin B1.
Fig. 3.
Fig. 3.
Mechanisms for age-associated up-regulation of PGE2 production and its interruption by vitamin E in Mφ. The binding of LPS to its receptor CD14 at the Mφ surface triggers its association with transmembrane protein TLR, mainly TLR2 and TLR4. MyD88, a cytoplasmic adaptor protein, responds to CD14/TLR stimulation by recruiting IL-1R-associated kinase (IRAK). Subsequent to activation of IRAK, TNFR-associated factor 6 (TRAF6) is phosphorylated and recruited to IRAK. Several tentative upstream kinases have been suggested to relay the signal to the IκB kinase (IKK) complex, including IKKα, IKKβ, and IKKγ/NF-κB essential modulator (NEMO), downstream of TRAF6. IKK is a major kinase responsible for the phosphorylation of IκB. Phosphorylated IκB is ubiquitinated further and eventually degraded, leaving the NF-κB dimer free, and translocated to nucleus. In murine Mφ, IκB degradation is increased because of aging, which results in an increased translocation of the NF-κB dimer to the nucleus. In the nucleus, NF-κB binds to the promoter region of the COX-2 gene and initiates the transcription. The resulting mRNA of COX-2 encodes the synthesis of the COX-2 enzyme. COX-2 catalyzes metabolism of AA to PGH2, which is isomerized further to PGE2. LPS-stimulated Mφ produce more ceramide in old than in young mice. Although only a LPS-induced activation pathway is illustrated here, age-associated up-regulation in COX-2 expression and transcription process is not stimulus-specific. Ceramide up-regulates COX-2 expression through NF-κB activation. The mechanism by which ceramide activates NF-κB degradation can only be speculated (shown as dotted lines) and remains to be determined. Vitamin E inhibits COX activity but has no effect on expression levels of protein and mRNA of COX-1 or COX-2. Vitamin E modulates this post-translational regulation, probably through its inhibitory effect on production of ONOO, a molecule shown to enhance COX activity but not affect COX enzyme expression. Mφ from old mice produce more NO than those from young mice. Vitamin E reduces NO production and might also do so to superoxide production and thus, ONOO synthesis. This has been reproduced with permission from Meydani et al. [88].
Fig. 4.
Fig. 4.
Working model: An age-associated up-regulation in adipocyte production of proinflammatory cytokines. We hypothesize that the age-related increase in adipocyte inflammation is a result of up-regulation of NF-κB, which is, in turn, a result of ceramide-induced modulation of the PKC-ζ-PPAR-γ-NF-κB pathway. Atypical PKC-ζ has been shown to activate NF-κB. PKC-ζ, in turn, can be activated by ceramide. PPAR-γ, which antagonizes NF-κB function, is a purported target of PKC-ζ. Our preliminary data showed that old adipocytes had higher ceramide content than young adipocytes, and inducing endogenous ceramide increased IL-6 production in young adipocytes to a level comparable with that of old. On the other hand, ceramide-induced IL-6 production was reduced by inhibition of NF-κB activity in old adipocytes to a level similar to that of young. Furthermore, reducing endogenous ceramide levels decreased IL-6 and TNF-α production. Further studies are needed to substantiate the hypothesized links in this network.

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