NF-ATp plays a prominent role in the transcriptional induction of Th2-type lymphokines

Calcium-dependent phosphatase calcineurin (CN) regulates the activation and nuclear translocation of NFAT. We identify here a novel CN-binding motif in one member of the NFAT family, NFATx, and a peptide based on this motif, Pep3. Pep3 binds CN and competes with wild-type NFATx for CN interaction. Amino acid mutations within Pep3 show that multiple amino acid residues are required for the effective functions of Pep3. Ectopic expression of Pep3 in a Th clone via a retrovirus-mediated gene transfer could selectively block the nuclear translocation of endogenous NFATx, whereas it had little effect on the nuclear translocation of another member of the NFAT family, NFATp. Furthermore, in transfection experiments, Pep3 also blocked the nuclear translocation of transfected NFATx, but not NFATp, in the B cell line M12, demonstrating specific inhibition of Pep3 for NFATx. Importantly, several cytokines produced by the T cell clone were severely repressed by ectopic Pep3, and indeed, the production of these cytokines was enhanced by the expression of wild-type NFATx. Our results show selective inhibition of NFATx activation and cytokine expression by Pep3 and suggest a new approach for studying the biology of each NFAT family member. This approach may provide an opportunity for pharmacological targeting of Ca2+-dependent signaling events.

Section: Discussionmentioning

confidence: 89%

Inhibition of NFATx Activation by an Oligopeptide: Disrupting the Interaction of NFATx with Calcineurin

Liu

Arai

2001

“…In contrast to our study, NFATc2-deficient mice exhibit enhanced OVA-induced pleural eosinophilia and increased allergic airway inflammation (25,26), suggesting a negative role for NFATc2 in the regulation of an in vivo Th2 immune response. However, this phenotype could be explained by a selective accumulation of cells with an activated or memory phenotype (CD44 high ) and T cell hyperproliferation in these mice (22,23). In contrast, expression of dnNFAT in T cells does not affect the naive CD4 ϩ T cell phenotype and inhibits transcription mediated by all four NFAT members (34).…”

Section: Discussionmentioning

confidence: 92%

“…NFATc1-deficient T cells show reduced proliferation, activation, and IL-4 production (20,21). NFATc2-deficient T cells exhibit hyperproliferation and dysregulated IL-4 gene expression and enhanced Th2 immune response (22)(23)(24)(25)(26). Mice lacking NFATc3 show impaired thymic development (27).…”

Section: Inhibition Of Nfat Specifically In T Cells Prevents Allergicmentioning

confidence: 99%

Inhibition of NFAT Specifically in T Cells Prevents Allergic Pulmonary Inflammation

Diehl¹,

Krahl²,

Rinaldi

et al. 2004

NFAT is a family of transcription factors important in the regulation of cytokine genes and is widely expressed in different lymphoid and nonlymphoid tissues. Consequently, the role of NFAT in CD4+ T cells during an in vivo immune response is not completely clear. In this study, we use transgenic mice expressing a dominant negative NFAT mutant exclusively in T cells to address the role of NFAT in T cells during a Th2 immune response in a model of allergic airway inflammation. We have observed that inhibition of NFAT in T cells results in a reduction of Ag-specific Th2 Ab levels and IL-4 production by CD4+ T cells. The accumulation of eosinophils in the bronchoalveolar lavage is delayed in dominant negative NFAT-transgenic mice. These mice are also more resistant to the development of lung pathology in response to allergen exposure. We, therefore, conclude that activation of NFAT in CD4+ T cells is required for the development of a Th2 immune response in vivo and allergic airway inflammation.

“…NFAT family consists of a number of members: NFATc1 (NFATc, NFAT2), NFATc2 (NFATp, NFAT1), NFATc3 (NFAT4, NFATx), and NFATc4 (NFAT3), each with discrete functions (32). The studies with mice deficient in either or both of these molecules have highlighted their role in immune response (33)(34)(35)(36)(37), demonstrating impaired lymphocyte proliferation in NFATc1-deficient lymphocytes with enhanced immune response in NFATc2-deficient animals. These studies on the role of these two members of NFATc family clearly demonstrate contrasting functions in control and regulation of immune response.…”

Section: Discussionmentioning

confidence: 99%

Recombinant p21 Protein Inhibits Lymphocyte Proliferation and Transcription Factors

Khanna

Plummer

Nilakantan

et al. 2005

Cellular proliferation determines the events leading to the initiation and development of inflammation, immune activation, cancer, atherogenesis, and other disorders associated with aberrant cell proliferation. Cyclin inhibitor p21 plays a unique role in limiting cell cycle progression. However, its effectiveness can only be demonstrated with direct in vitro and in vivo delivery to control aberrant proliferation. We demonstrate that using a protein-transducing domain p21 protein a) localizes within the nuclear compartments of cells, b) interacts with transcription factors, NF-κB, and NFATs (NFATc and NFATp), and c) inhibits lymphocyte proliferation and expression of proinflammatory cytokines. This study using lymphocyte proliferation as a model suggests that the recombinant p21 protein can directly be delivered as a therapeutic protein to provide a novel, viable, and powerful strategy to limit proliferation, inflammation, alloimmune activation, cancer, and vascular proliferative disorders such as atherosclerosis.