Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T cells from patients with systemic lupus erythematosus are characterized by decreased expression of CD3zeta-chain and increased expression of FcRgamma-chain, which becomes part of the CD3 complex and contributes to aberrant signaling. Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response. Therefore, PP2A serves as a central determinant of abnormal T cell function in human lupus and may represent an appropriate treatment target.
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PMID:PP2A dephosphorylates Elf-1 and determines the expression of CD3zeta and FcRgamma in human systemic lupus erythematosus T cells. 1871 41

IL-2 plays a key role in setting the balance between immunity and tolerance. This cytokine has a dual role as the regulator of the two main phases of the immune response (proliferative and suppressive). Likewise, activation induced cell death and the induction and maintenance of regulatory T cells are the tolerance mechanisms regulated by IL-2, which convey the link between IL-2 abnormalities and the development of autoimmune disorders, such as systemic lupus erythematosus (SLE). Particularly, in SLE murine models and in humans, deficiency in IL-2 synthesis and activity has been proven. Diverse signaling pathways abnormalities (TCR, NF-kappaBeta, NF-AT) have been involved in the IL-2 transcriptional dysregulation displayed by T cells from SLE patients, and its functional relevance as part of the physiopathogenic scheme has been shown. Aberrant expression and activity of multiple IL-2 transcriptional factors, such as c-fos, and predominantly, CREM and CREB have been involved in this immune dysregulation. Diverse alterations in signaling kinases and phosphatases (PKA, PP2A, CAMKIV) and the modulation by epigenetic mechanisms have been related to the altered CREM/pCREB index. The synergic effect of multiple abnormalities in the transcriptional factors previously mentioned has been shown to be of functional relevance in lupus.
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PMID:Interleukin 2 and systemic lupus erythematosus: beyond the transcriptional regulatory net abnormalities. 1926 52

B-cell activating factor (BAFF) is involved in not only physiology of normal B cells, but also pathophysiology of aggressive B cells related to malignant and autoimmune diseases. Rapamycin, a lipophilic macrolide antibiotic, has recently shown to be effective in the treatment of human lupus erythematosus. However, how rapamycin inhibits BAFF-stimulated B-cell proliferation and survival has not been fully elucidated. Here, we show that rapamycin inhibited human soluble BAFF (hsBAFF)-induced cell proliferation and survival in normal and B-lymphoid (Raji and Daudi) cells by activation of PP2A and inactivation of Erk1/2. Pretreatment with PD98059, down-regulation of Erk1/2, expression of dominant negative MKK1, or overexpression of wild-type PP2A potentiated rapamycin's suppression of hsBAFF-activated Erk1/2 and B-cell proliferation/viability, whereas expression of constitutively active MKK1, inhibition of PP2A by okadaic acid, or expression of dominant negative PP2A attenuated the inhibitory effects of rapamycin. Furthermore, expression of a rapamycin-resistant and kinase-active mTOR (mTOR-T), but not a rapamycin-resistant and kinase-dead mTOR-T (mTOR-TE), conferred resistance to rapamycin's effects on PP2A, Erk1/2 and B-cell proliferation/viability, implying mTOR-dependent mechanism involved. The findings indicate that rapamycin inhibits BAFF-stimulated cell proliferation/survival by targeting mTOR-mediated PP2A-Erk1/2 signaling pathway in normal and neoplastic B-lymphoid cells. Our data highlight that rapamycin may be exploited for preventing excessive BAFF-induced aggressive B-cell malignancies and autoimmune diseases.
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PMID:Rapamycin inhibits BAFF-stimulated cell proliferation and survival by suppressing mTOR-mediated PP2A-Erk1/2 signaling pathway in normal and neoplastic B-lymphoid cells. 2611 61