TNF{alpha} That Are Potent Inhibitors of Classes of Thalidomide Analogues T Cell Activation by Two Distinct Differential Cytokine Modulation and (original) (raw)
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The Journal of Immunology, 1999
TNF-␣ mediates both protective and detrimental manifestations of the host immune response. Our previous work has shown thalidomide to be a relatively selective inhibitor of TNF-␣ production in vivo and in vitro. Additionally, we have recently reported that thalidomide exerts a costimulatory effect on T cell responses. To develop thalidomide analogues with increased anti-TNF-␣ activity and reduced or absent toxicities, novel TNF-␣ inhibitors were designed and synthesized. When a selected group of these compounds was examined for their immunomodulatory activities, different patterns of cytokine modulation were revealed. The tested compounds segregated into two distinct classes: one class of compounds, shown to be potent phosphodiesterase 4 inhibitors, inhibited TNF-␣ production, increased IL-10 production by LPS-induced PBMC, and had little effect on T cell activation; the other class of compounds, similar to thalidomide, were not phosphodiesterase 4 inhibitors and markedly stimulated T cell proliferation and IL-2 and IFN-␥ production. These compounds inhibited TNF-␣, IL-1, and IL-6 and greatly increased IL-10 production by LPS-induced PBMC. Similar to thalidomide, the effect of these agents on IL-12 production was dichotomous; IL-12 was inhibited when PBMC were stimulated with LPS but increased when cells were stimulated by cross-linking the TCR. The latter effect was associated with increased T cell CD40 ligand expression. The distinct immunomodulatory activities of these classes of thalidomide analogues may potentially allow them to be used in the clinic for the treatment of different immunopathological disorders. The Journal of Immunology, 1999, 163: 380 -386.
1999
TNF-␣ mediates both protective and detrimental manifestations of the host immune response. Our previous work has shown thalidomide to be a relatively selective inhibitor of TNF-␣ production in vivo and in vitro. Additionally, we have recently reported that thalidomide exerts a costimulatory effect on T cell responses. To develop thalidomide analogues with increased anti-TNF-␣ activity and reduced or absent toxicities, novel TNF-␣ inhibitors were designed and synthesized. When a selected group of these compounds was examined for their immunomodulatory activities, different patterns of cytokine modulation were revealed. The tested compounds segregated into two distinct classes: one class of compounds, shown to be potent phosphodiesterase 4 inhibitors, inhibited TNF-␣ production, increased IL-10 production by LPS-induced PBMC, and had little effect on T cell activation; the other class of compounds, similar to thalidomide, were not phosphodiesterase 4 inhibitors and markedly stimulated T cell proliferation and IL-2 and IFN-␥ production. These compounds inhibited TNF-␣, IL-1, and IL-6 and greatly increased IL-10 production by LPS-induced PBMC. Similar to thalidomide, the effect of these agents on IL-12 production was dichotomous; IL-12 was inhibited when PBMC were stimulated with LPS but increased when cells were stimulated by cross-linking the TCR. The latter effect was associated with increased T cell CD40 ligand expression. The distinct immunomodulatory activities of these classes of thalidomide analogues may potentially allow them to be used in the clinic for the treatment of different immunopathological disorders.
Journal of immunology (Baltimore, Md. : 1950), 1999
TNF-alpha mediates both protective and detrimental manifestations of the host immune response. Our previous work has shown thalidomide to be a relatively selective inhibitor of TNF-alpha production in vivo and in vitro. Additionally, we have recently reported that thalidomide exerts a costimulatory effect on T cell responses. To develop thalidomide analogues with increased anti-TNF-alpha activity and reduced or absent toxicities, novel TNF-alpha inhibitors were designed and synthesized. When a selected group of these compounds was examined for their immunomodulatory activities, different patterns of cytokine modulation were revealed. The tested compounds segregated into two distinct classes: one class of compounds, shown to be potent phosphodiesterase 4 inhibitors, inhibited TNF-alpha production, increased IL-10 production by LPS-induced PBMC, and had little effect on T cell activation; the other class of compounds, similar to thalidomide, were not phosphodiesterase 4 inhibitors and...
Immunomodulation by thalidomide and thalidomide analogues
Annals of the rheumatic diseases, 1999
Tumour necrosis factor α (TNFα), a key cytokine involved in the host immune response, also contributes to the pathogenesis of both infectious and autoimmune diseases. To ameliorate the pathology resulting from TNFα in these clinical settings, strategies for the inhibition of this ...
Pharmacological Properties of Thalidomide and its Analogues
Recent Patents on Inflammation & Allergy Drug Discovery, 2010
Thalidomide and its immunomodulatory imide drugs (IMiDs) analogues CC-5013 (Revlimid™, Lenalidomide) and CC-4047 (Actimid™, Pomalidomide) have been used as anti-inflammatory and anticancerous drugs in the recent years. Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor-(TNF-), interleukins (IL) 1 , 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). They also costimulate primary human T, NKT and NK lymphocytes inducing their proliferation, cytokine production, and cytotoxic activity. On the other hand, the compounds are anti-angiogenic, anti-proliferative, and pro-apoptotic. Thalidomide analogues have been used as inhibitors of glucosidase and could be potential drugs for diabetes treatment. In this review, we explore the current trend of the different structures, the new patents, and the possible new applications in different pathologies.
Selection of novel analogs of thalidomide with enhanced tumor necrosis factor α inhibitory activity
Molecular Medicine
Tumor necrosis factor alpha (TNF alpha) is thought to mediate both protective and detrimental manifestations of the inflammatory response. Recently, thalidomide (alpha-N-phthalimidoglutarimide) was shown to partially inhibit monocyte TNF alpha production (by 50-70%) both in vivo and in vitro. More efficient inhibition of TNF alpha may, however, be necessary to rescue the host from more acute and extensive toxicities of TNF alpha-mediated inflammation. Three structural analogues of thalidomide were selected for study based on increased activity against TNF alpha production. The parent drug and the analogs were tested in vitro in human peripheral blood mononuclear cell cultures for their effects on lipopolysaccharide (LPS) induced cytokine protein and mRNA production using ELISAs and Northern blot hybridization. The in vitro effects of the drugs were then confirmed in vivo in a mouse model of LPS induced lethality. The new compounds (two esters and one amide) showed increased inhibiti...
Recent Developments of Thalidomide Derivatives Possessing Anti-Inflammatory Activity
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2010
Thalidomide (-N-phthalimidoglutarimide) was a widely used drug in the late 1950s as a hypnotic/ sedative agent. Thalidomide was subsequently withdrawn from the market due to teratogenicity in the early 1960s. Surprisingly, even after the initial impact of the thalidomide disaster, the drug was still used in the therapy of many diseases, and research studies in the field of thalidomide derivatives have significantly increased because of its tumor necrosis factor (TNF-) production regulating effect. Recently, novel thalidomide derivatives have been synthesized as anti-inflammatory lead-candidates. This review will summarize the recent development of thalidomide derivatives which possess antiinflammatory activity.
Journal of Pharmacology and Experimental Therapeutics, 2003
CC-4047 (Actimid) and CC-5013 (Revimid) belong to a class of thalidomide analogs collectively known as the immunomodulatory drugs (IMiDs), which are currently being assessed in the treatment of patients with multiple myeloma and other cancers. IMiDs potently enhance T cell and natural killer cell responses and inhibit tumor necrosis factor-␣, interleukin (IL)-1, and IL-12 production from LPS-stimulated peripheral blood mononuclear cells. However, the molecular mechanism of action for these compounds is unknown. Herein, we report on the ability of the IMiDs to up-regulate production of IL-2 from activated human CD4 ϩ and CD8 ϩ peripheral blood T cells, production of IL-2 and IFN-␥ from T helper (Th)1-type cells, and production of IL-5 and IL-10 from Th2-type cells. Elevation of IL-2 production from Jurkat T cells was observed as early as 6 h poststimulation and correlated with an increase in IL-2 promoter activity that was dependent upon the proximal but not the distal AP-1 binding site. The IMiDs enhanced AP-1-driven transcriptional activity 2-to 4-fold after 6 h of T cell stimulation, and their relative potencies for AP-1 activation correlated with their potencies for increased IL-2 production in Jurkat T cells and in CD4 ϩ or CD8 ϩ human peripheral blood T cells. The most potent of these IMiDs, CC-4047, had no effect on nuclear factor of activated T cells transcriptional activity, calcium signaling, or phosphorylation of extracellular signal-regulated kinase 1/2, c-Jun NH 2-terminal kinase 1/2, p38 mitogen-activated protein kinase, or c-Jun/Jun D in Jurkat T cells. These data suggest that IMiDs increase T cell cytokine production by potentiating AP-1 transcriptional activity. The IMiDs are a class of small molecule analogs of thalidomide originally studied for their ability to potently inhibit TNF-␣ from LPS-stimulated human PBMCs in vitro (Muller et al., 1999). On a molar basis, they are up to 200,000-fold more potent than thalidomide at inhibiting TNF-␣ production. In addition to suppressing TNF-␣ production, IMiDs also inhibit IL-1, IL-12, and IL-6 production and elevate IL-10 production from LPS-stimulated PBMCs, but elevate TNF-␣ production, IL-12 production, and CD40L expression, and decrease IL-10 production in anti-CD3-stimulated PB-MCs (Corral et al., 1999). Like thalidomide, IMiDs enhance IL-2 and IFN-␥ production and proliferation of anti-CD3stimulated T cells in vitro (Haslett et al., 1998; Corral et al., 1999; Davies et al., 2001). The stimulatory effect of thalidomide on T cell proliferation was found to be dependent on the induction of endogenous IL-2 production (Haslett et al., 1998). IMiDs have also been shown to inhibit proliferation of various MM cell lines by inducing either apoptosis or cell cycle arrest in G 0 /G 1 phase (Hideshima et al., 2000). Thalidomide and IMiD-treated PBMCs from patients with MM showed increases in NK cell numbers and NK lytic activity against autologous MM cells (Davies et al., 2001). Increases This work was supported by Celgene Corporation. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.