Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental allergic encephalomyelitis (EAE) is a CD4(+) Th1 cell-mediated inflammatory demyelinating autoimmune disease of the CNS that serves as an animal model for multiple sclerosis (MS). IL-12 is a proinflammatory cytokine that plays a crucial role in the induction of neural Ag-specific Th1 differentiation and pathogenesis of CNS demyelination in EAE and MS. Curcumin (1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a naturally occurring polyphenolic phytochemical isolated from the rhizome of the medicinal plant Curcuma longa. It has profound anti-inflammatory activity and been traditionally used to treat inflammatory disorders. In this study we have examined the effect and mechanism of action of curcumin on the pathogenesis of CNS demyelination in EAE. In vivo treatment of SJL/J mice with curcumin significantly reduced the duration and clinical severity of active immunization and adoptive transfer EAE. Curcumin inhibited EAE in association with a decrease in IL-12 production from macrophage/microglial cells and differentiation of neural Ag-specific Th1 cells. In vitro treatment of activated T cells with curcumin inhibited IL-12-induced tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT3 and STAT4 transcription factors. The inhibition of Janus kinase-STAT pathway by curcumin resulted in a decrease in IL-12-induced T cell proliferation and Th1 differentiation. These findings highlight the fact that curcumin inhibits EAE by blocking IL-12 signaling in T cells and suggest its use in the treatment of MS and other Th1 cell-mediated inflammatory diseases.
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PMID:Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes. 1205 72

PTEN is a tumor suppressor gene mutated in many human sporadic cancers and in hereditary cancer syndromes such as Cowden disease, Bannayan-Zonana syndrome and Lhermitte-Duclos disease. The major substrate of PTEN is PIP3, a second messenger molecule produced following PI3K activation induced by variety of stimuli. PIP3 activates the serine-threonine kinase PKB/Akt which is involved in anti-apoptosis, proliferation and oncogenesis. In mice, heterozygosity for a null mutation of Pten (Pten(+/-) mice) frequently leads to the development of a variety of cancers and autoimmune disease. Homozygosity for the null mutation (Pten (-/-) mice) results in early embryonic lethality, precluding the functional analysis of Pten in various organs. To investigate the physiological functions of Pten in viable mice, various tissue-specific Pten mutations have been generated using the Cre-loxP system. This review will summarize the phenotypes of conditional mutant mice lacking Pten function in specific tissues, and discuss how these phenotypes relate to the physiological roles of Pten in various organ systems.
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PMID:Physiological functions of Pten in mouse tissues. 1265 46

Here we show that Janus kinase (JAK) 3 is an important molecular target for treatment of autoimmune insulin-dependent (type 1) diabetes mellitus. The rationally designed JAK3 inhibitor JANEX-1 exhibited potent immunomodulatory activity and delayed the onset of diabetes in the NOD mouse model of autoimmune type 1 diabetes. Whereas 60% of vehicle-treated control NOD mice became diabetic by 25 weeks, the incidence of diabetes at 25 weeks was only 9% for NOD females treated with daily injections of JANEX-1 (100 mg/kg/day) from Week 10 through Week 25 (P = 0.007). Furthermore, JANEX-1 prevented the development of insulitis and diabetes in NOD-scid/scid females after adoptive transfer of splenocytes from diabetic NOD females. Chemical inhibitors such as JANEX-1 may provide the basis for effective treatment modalities against human type 1 diabetes. To our knowledge, this is the first report of the immunosuppressive activity of a JAK3 inhibitor in the context of an autoimmune disease.
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PMID:Targeting JAK3 with JANEX-1 for prevention of autoimmune type 1 diabetes in NOD mice. 1270 8

Although HIV infection is often associated with several rheumatic diseases, the coexistence of this retroviral infection and systemic lupus erythematosus (SLE) is extremely uncommon. Generally, HIV-related immunosuppression improves SLE symptoms, and antiretroviral therapy may lead to an autoimmune disease flare subsequent to the increase of circulating CD4+ cell number. Two HIV-infected female patients with SLE and discoid lupus erythematosus (DLE) diagnosed a few months after the highly active antiretroviral therapy initiation, are described. To our knowledge, this is the second case of DLE and the twenty-seventh case of SLE reported to date in association with HIV infection.
Int J STD AIDS 2003 May
PMID:Systemic and discoid lupus erythematosus in HIV-infected patients treated with highly active antiretroviral therapy. 1507 26

In susceptible mice, mercuric chloride induces a systemic autoimmune disease characterized by increased serum levels of immunoglobulin (Ig) G1 and IgE, production of anti-nucleolar autoantibodies (ANolA) and formation of renal IgG deposits. We have previously hypothesized that mercury confers more adverse immunological effects on those mouse strains, which are genetically prone to develop spontaneous autoimmune diseases than on normal strains. In this study, we tested our hypothesis in tight skin 1 (Tsk1/+) mice, a murine model for human scleroderma. As a support for our hypothesis, we observed that in Tsk1/+ mice, B cells were spontaneously hyperactive and that treatment with mercury induced a strong immune/autoimmune response in these mice, but not in their non-Tsk (+/+) littermates. This response was characterized by the formation of high numbers of splenic IgG1, IgG2b and IgG3 antibody-secreting cells, increased serum levels of IgE, production of IgG1 antibodies against single-stranded DNA (ssDNA), trinitrophenol (TNP) as well as thyroglobulin and the development of renal IgG1 deposits. Neither Tsk1/+ mice nor F1 hybrid crosses between this strain, and mercury susceptible B10.S (H-2(s)) were able to produce IgG1-ANolA in response to mercury. Moreover, mercury-induced immune activation in Tsk1/+ was not able to potentiate the progression of skin fibrosis in this strain. Thus, exposure to mercury accelerates the immune dysregulation, but not the development of skin fibrosis in Tsk1/+ mice.
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PMID:Mercuric chloride induces a strong immune activation, but does not accelerate the development of dermal fibrosis in tight skin 1 mice. 1514 57

Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of multiple sclerosis (MS). Quercetin (3,3'4',5,7-pentahydroxy flavone) is a flavonoid phytoestrogen that has profound anticancer and anti-inflammatory activities. In this study, we show that in vivo treatment of SJL/J mice with quercetin (i.p. 50 or 100 microg every other day) ameliorates EAE in association with the inhibition of IL-12 production and neural antigen-specific Th1 differentiation. In vitro treatment of activated T cells with quercetin blocks IL-12-induced tyrosine phosphorylation of JAK2, TYK2, STAT3, and STAT4, resulting in a decrease in IL-12-induced T cell proliferation and Th1 differentiation. These findings highlight the fact that quercetin ameliorates EAE by blocking IL-12 signaling and Th1 differentiation and suggest its use in the treatment of MS and other Th1 cell-mediated autoimmune diseases.
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PMID:Quercetin, a flavonoid phytoestrogen, ameliorates experimental allergic encephalomyelitis by blocking IL-12 signaling through JAK-STAT pathway in T lymphocyte. 1535 13

During the past year, crystal structures of the PDK-1, ITK, Aurora-A, c-KIT and FLT-3 protein kinases in complex with several ATP-competitive inhibitors have been determined. Some structures have crystallized in catalytically active conformations, whereas others appear to be in inactive or native conformations. The differences between these two classes of structures provide further understanding of how kinase activity may be self-regulated in the cellular environment and how phosphorylation can modulate signalling at a molecular level. All of these structures provide a basis for designing selective protein kinase inhibitors of use in the treatment of cancer and autoimmune disease.
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PMID:Novel protein kinases and molecular mechanisms of autoinhibition. 1558 94

Protein kinase B (PKBalpha/Akt1) a PI3K-dependent serine-threonine kinase, promotes T cell viability in response to many stimuli and regulates homeostasis and autoimmune disease in vivo. To dissect the mechanisms by which PKB inhibits apoptosis, we have examined the pathways downstream of PKB that promote survival after cytokine withdrawal vs Fas-mediated death. Our studies show that PKB-mediated survival after cytokine withdrawal is independent of protein synthesis and the induction of NF-kappaB. In contrast, PKB requires de novo gene transcription by NF-kappaB to block apoptosis triggered by the Fas death receptor. Using gene-deficient and transgenic mouse models, we establish that NF-kappaB1, and not c-Rel, is the critical signaling molecule downstream of the PI3K-PTEN-PKB signaling axis that regulates lymphocyte homeostasis.
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PMID:NF-kappaB couples protein kinase B/Akt signaling to distinct survival pathways and the regulation of lymphocyte homeostasis in vivo. 1614 25

Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated autoimmune disease model of multiple sclerosis (MS). IL-12 plays a crucial role in the pathogenesis of EAE/MS and inhibition of IL-12 production or IL-12 signaling was effective in preventing EAE. Cyclooxygenase (COX-2) is a key enzyme promoting inflammation in rheumatoid arthritis and tumor induced angiogenesis. Recent studies have shown that COX-2 inhibitors prevent EAE, however, their mechanism of action is not fully understood. In this study, we show that in vivo treatment (i.p.) with 100 mug COX-2 selective inhibitors (LM01, LM08, LM11, and NS398), on every other day from day 0 to 30, significantly reduced the incidence and severity of EAE in SJL/J and C57BL/6 mice. Further analyses showed that the COX-2 inhibitors reduced neural antigen-induced IL-12 production, T cell proliferation and Th1 differentiation ex vivo and in vitro. The COX-2 inhibitors also decreased IL-12-induced T cell responses through blocking tyrosine phosphorylation of JAK2, TYK2, STAT3, and STAT4 proteins in T cells. These results demonstrate that COX-2 inhibitors ameliorate EAE in association with the modulation of IL-12 signaling through JAK-STAT pathway leading to Th1 differentiation and suggest their use in the treatment of MS and other Th1 cell-mediated autoimmune diseases.
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PMID:COX-2 inhibitors modulate IL-12 signaling through JAK-STAT pathway leading to Th1 response in experimental allergic encephalomyelitis. 1641 5

Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated autoimmune disease model of multiple sclerosis (MS). Vitamin D deficiency is commonly observed in MS patients and vitamin D supplements reduce the clinical symptoms of EAE and MS. Earlier studies have shown that in vivo treatment with vitamin D analogs ameliorates EAE in association with the inhibition of IL-12 production and Th1 differentiation. The mechanisms in the regulation of Th1 response by vitamin D in EAE/MS are, however, not known. We show that in vivo treatment of C57BL/6 and SJL/J mice (i.p.) with 100 ng of 1,25 dihydroxyvitamin D3, on every other day from Day 0-30, ameliorates EAE in association with the inhibition of IL-12 production and neural antigen-specific Th1 response. In vitro treatment with 1,25(OH)2D3 inhibited IFNgamma-induced tyrosine phosphorylation of STAT1, without affecting JAK2, in EOC-20 microglial cells. Treatment of activated T cells with 1,25(OH)2D3 also inhibited the IL-12-induced tyrosine phosphorylation of JAK2, TYK2, STAT3, and STAT4 in association with a decrease in T cell proliferation in vitro. These findings highlight the fact that vitamin D modulates JAK-STAT signaling pathway in IL-12/IFNgamma axis leading to Th1 differentiation and further suggest its use in the treatment of MS and other Th1 cell-mediated autoimmune diseases.
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PMID:1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNgamma axis leading to Th1 response in experimental allergic encephalomyelitis. 1654 67


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