Sergei Atamas - Academia.edu (original) (raw)

Papers by Sergei Atamas

Fibrogenesis & Tissue Repair, Jul 25, 2011

Biopolymers & Cell, May 20, 1989

Scientific Reports, Aug 19, 2022

American Journal of Respiratory Cell and Molecular Biology, Sep 1, 2006

arXiv (Cornell University), Dec 13, 2011

Journal of Biological Chemistry, Jul 1, 2015

Pediatric Research, Aug 1, 2006

Current Rheumatology Reports, Mar 17, 2018

Purpose of Review-Premature activation of aging-associated molecular mechanisms is emerging as an... more Purpose of Review-Premature activation of aging-associated molecular mechanisms is emerging as an important contributor to many diseases, including scleroderma. Among central regulators of the aging process are a group of histone deacetylases called sirtuins (SIRTs). Recent findings implicate these molecules as pathophysiological players in scleroderma skin and lung fibrosis. The goal of this article is to review recent studies on the involvement of SIRTs in scleroderma from the perspective of aging-related molecular mechanisms. Recent Findings-Despite a degree of controversy in this rapidly developing field, the majority of data suggest that SIRT levels are decreased in tissues from patients with scleroderma compared to healthy controls as well as in animal models of scleroderma. Molecular studies reveal several mechanisms through which declining SIRT levels contribute to fibrosis, with the most attention given to modulation of the TGF-β signaling pathway. Activation of SIRTs in cell culture and in animal models elicits antifibrotic effects. Summary-Declining SIRT levels and activity are emerging as pathophysiological contributors to scleroderma. Restoration of SIRTs may be therapeutic in patients with scleroderma.

American Journal of Respiratory Cell and Molecular Biology, Dec 1, 2013

American Journal of Hematology, 2000

Journal of Immunology, Apr 1, 2011

Interleukin (IL)-33 and its receptor ST2 have been recently implicated as critical regulators of ... more Interleukin (IL)-33 and its receptor ST2 have been recently implicated as critical regulators of responses to injury and of ensuing inflammation. The roles of IL-33 and ST2 in pulmonary inflammation and scarring remain unclear. We analyzed bronchoalveolar lavage (BAL) from patients with idiopathic pulmonary fibrosis (IPF), a disease characterized by inflammation, with known elevated levels of IL-8 and excessive collagen deposition in the lungs. IL-33 was not found in BAL from 5 controls but was found in 7 out of 11 IPF samples, at 10.0 ± 3.2 pg/ml. Soluble ST2 was found in BAL from healthy controls at 93.2 ± 82.1 pg/ml, and in all IPF samples at 352.1 ± 135.2 pg/ml (p < 0.05, Mann-Whitney U test). The elevation of IL-33 in BAL suggested that this cytokine may act directly on pulmonary epithelial cells and through this action contribute to inflammation. Cultured human primary pulmonary epithelial cells were stimulated with rhIL-33, and the levels of pro-inflammatory cytokines IL-6, IL-8, MIP-1α, and TNF-α in cell culture media were analyzed by ELISA. Of the analyzed cytokines, only the levels of IL-8 were increased by 2.0 ± 0.2 fold at 24 h and 1.7 ± 0.2 fold at 48 h. In conclusion, levels of IL-33 and ST2 are elevated in the lungs of IPF patients; IL-33 may contribute to inflammation and fibrosis by activating IL-8 production in pulmonary epithelium.

Journal of Immunology, May 1, 2012

Previous reports have been inconsistent on whether Interleukin (IL)-33 necessarily promotes Th2 e... more Previous reports have been inconsistent on whether Interleukin (IL)-33 necessarily promotes Th2 effects in vivo. This diversity of findings may be due to post-synthetic processing of IL-33. We compared the in vivo effects of full-length mouse (flm) and mature mouse (mm) IL-33 utilizing replication-deficient adenovirus (AdV)-mediated gene delivery. mmIL-33 promoted pulmonary eosinophilia, neutrophilia, and significant elevations in IL-4, IL-5, and IL-13 compared to AdV-NULL-infected controls (p < 0.05 in all cases), whereas flmIL-33 had no such effects. A possibility was considered that flmIL-33 may modulate the effects of a prototypic Th2 cytokine, IL-4. The effects of AdV-mediated gene delivery of IL-4 were compared with the effects of combined flmIL-33 and mIL-4. In the latter case, a bicistronic AdV construct encoding flmIL-33 and mIL-4 was used to ensure co-localization of expression of both cytokines. On day 7 after instillation of the viral particles, IL-4-expressing mice had elevated eosinophils and neutrophils in their BAL, and animals expressing both flmIL-33 and IL-4 had yet significantly more BAL eosinophils and neutrophils compared with IL-4-expressing mice (p < 0.05). Similar potentiating effects of flmIL-33 were observed on IL-4-driven increases in pulmonary cytokines TNF-α, IL-5, IL-13, MCP-1, and in goblet cell hyperplasia. These results suggest that although full-length IL-33 has no independent pro-Th2 effect on the lung, it potentiates such effects of IL-4.

Journal of Immunology, Apr 1, 2009

Interstitial lung disease, a combination of pulmonary inflammation and fibrosis, is deadly and oc... more Interstitial lung disease, a combination of pulmonary inflammation and fibrosis, is deadly and occurs idiopathically or as a complication of autoimmune rheumatic diseases (scleroderma, rheumatoid arthritis, poly- and dermatomyositis, lupus). T cells often accumulate in the lungs of such patients. Previous reports suggested that αV-containing integrins may activate TGF-β and facilitate fibrosis. Whether pulmonary T cells utilize such integrins in interstitial lung disease is not clear. Expression of integrins αVβ3 (ITGAVB3) or αVβ5 (ITGAVB5) on pulmonary T cells was observed by double-stain immunofluorescence confocal microscopy in six out of six patients with scleroderma lung disease, as well as in the animal models of pulmonary CCL18 overexpression that manifests in selective T lymphocytic infiltration of the lungs and T cell-dependent pulmonary fibrosis. Flow cytometry of bronchoalveolar lavage T cells confirmed expression of integrins on more than 10% (up to 50%) of pulmonary T cells in 14 of 25 scleroderma patients and in all CCL18-overexpressing mice; Q-PCR experiments confirmed elevated integrin mRNAs in purified BAL T cells. There was no expression of ITGAVB3 or ITGAVB5 on T cells from the lungs of healthy volunteers or control mice. Injections of anti-ITGB3 blocking antibody or genetic deficiency of ITGB3 protected mice from CC18-induced inflammation and fibrosis. Jurkat cells that were forced to overexpress ITGAVB3 or ITGAVB5 induced Smad2 phosphorylation and nuclear translocation, and increases in collagen and α-smooth muscle actin expression in co-cultures with primary lung fibroblasts. Blocking anti-TGF-β antibodies attenuated such regulation in cell co-cultures. Thus, expression of integrins on pulmonary T cells contributes to interstitial lung disease by promoting T cell infiltration, TGF-β activation, and fibrosis.

Journal of Immunology, Apr 1, 2009

We have previously shown that IL-4δ2, a naturally occurring in humans and other species splice va... more We have previously shown that IL-4δ2, a naturally occurring in humans and other species splice variant of IL-4, competes with IL-4 for receptor binding and inhibits some of IL-4 effects on lymphocytes and monocytes. Numerous groups reported that the levels and the ratio of IL-4δ2 and IL-4 mRNAs change in immune, inflammatory, and infectious diseases. It has been suggested that recombinant human (rh) IL-4δ2 can be used therapeutically to neutralize the harmful effects of excess IL-4 in vivo, although it was not clear whether IL-4δ2 mRNA expressing cells secrete IL-4δ2 protein. Transfection of HEK293 or Jurkat cells with IL-4δ2-encoding constructs resulted in IL-4δ2 protein secretion confirmed by LC/MS, ELISA, and Western blotting. To investigate whether IL-4δ2 has no independent activity and acts only as an inhibitor of IL-4, we overexpressed human IL-4δ2 in mouse lungs. Adenovirus-mediated gene delivery of IL-4δ2 caused lymphocytic infiltration similar to that in IL-4-overexpressing mice, as well as proinflammatory/Th1 changes in pulmonary milieu, with the induced levels of TNF-α, IL-1, IFN-γ, IL-12p40, and MCP-1 significantly exceeding those induced by gene delivery of IL-4. Germline deficiency of STAT6 had no effect, whereas deficiency of IL-4Rα significantly attenuated IL-4δ2-induced or IL-4-induced changes in the lungs. Stimulation of primary human T cells or PBMC, but not fibroblasts or A549 cells, with rhIL-4δ2 induced phosphorylation of Jak1, Jak3, and Tyk2, but not of STAT6. IL-4δ2 potently induced production of MCP-1 in human T cells and upregulated IL-4δ2 mRNA production in an autocrine fashion by several hundred fold. Thus, IL-4δ2 is secreted as a protein, acts as a potent autocrine regulator of inflammation and immunity in an IL-4Rα-dependent STAT6-independent fashion, and is a potential novel target for future therapies.

Journal of Immunology, Apr 1, 2011

Activities of T lymphocytes are centrally regulated by interactions between multiple members of t... more Activities of T lymphocytes are centrally regulated by interactions between multiple members of the TNF/TNF-R family. TRAIL is a member of the TNF family with pro-apoptotic activity. The only signaling TRAIL receptor in mice is death receptor (DR) 5. CCL18, a chemokine with selective chemotactic activity on T lymphocytes, is known for its involvement in pulmonary inflammation and fibrosis associated with autoimmune diseases. We measured soluble TRAIL in bronchoalveolar lavage (BAL) fluids. The levels of TRAIL were significantly elevated (p < 0.01, ANOVA) in BAL from 16 patients with scleroderma lung disease (211±110 pg/ml) compared to 16 patients without lung involvement (115±58 pg/ml), or 8 healthy controls (73±41 pg/ml). To determine whether TRAIL is important for CCL18-induced pulmonary infiltration of lymphocytes, recombinant adenovirus-mediated gene delivery of CCL18 was performed in TRAIL KO, DR5 KO, and WT mice. Overexpression of CCL18 caused profound pulmonary lymphocytic infiltration in WT and TRAIL KO mice, compared to control mice infected with AdV-NULL. In contrast, infiltration of T lymphocytes was completely abrogated in CCL18-expressing DR5 KO mice, based on lung histology. Thus, the levels of TRAIL are elevated in the lungs of patients with autoimmunity-associated inflammation and fibrosis, yet TRAIL does not appear to be involved in the CCL18-mediated T lymphocytic infiltration, whereas its receptor DR5 is required for such T cell response to CCL18.

Science Translational Medicine, May 30, 2012

Theoretical Biology and Medical Modelling, Dec 1, 2012

Journal of Leukocyte Biology, Feb 1, 2011

IL-4␦2 is a natural splice variant of IL-4 that lacks the region encoded by the second exon. Nume... more IL-4␦2 is a natural splice variant of IL-4 that lacks the region encoded by the second exon. Numerous reports have suggested that the expression levels of IL-4␦2 change in various diseases, especially those with pulmonary involvement, but the in vivo effects of this splice variant have never been studied. Replication-deficient, AdV-mediated gene delivery of mIL-4␦2 to mouse lungs in vivo was used, and the effects compared with similar adenoviral delivery of mIL-4 or with infection with a noncoding NULL viral construct. Overexpression of IL-4␦2 or IL-4 caused pulmonary infiltration by T and B lymphocytes, whereas in contrast to IL-4, IL-4␦2 did not induce eosinophilia or goblet cell hyperplasia. Microarray analysis of global gene expression revealed that IL-4␦2 and IL-4 had differential effects on gene expression. These splice variants also differentially regulated pulmonary levels of the cytokines TNF-␣, eotaxin, IL-1␣, IFN-␥, and MCP-1, whereas both tended to increase total lung collagen modestly. Pulmonary infiltration by lymphocytes in response to overexpression of IL-4␦2 was attenuated but not abrogated completely by germline deficiency of IL-4R␣ or STAT6, whereas deficiency of endogenous IL-4 had no effect. Thus, IL-4␦2 promotes lymphocytic inflammation in vivo (although differentially from IL-4, in part), and the effects of IL-4␦2 are not mediated by endogenous IL-4. Differential targeting of IL-4␦2 and IL-4 may therefore be considered in developing future therapeutic agents.

Fibrogenesis & Tissue Repair, Jul 25, 2011

Biopolymers & Cell, May 20, 1989

Scientific Reports, Aug 19, 2022

American Journal of Respiratory Cell and Molecular Biology, Sep 1, 2006

arXiv (Cornell University), Dec 13, 2011

Journal of Biological Chemistry, Jul 1, 2015

Pediatric Research, Aug 1, 2006

Current Rheumatology Reports, Mar 17, 2018

Purpose of Review-Premature activation of aging-associated molecular mechanisms is emerging as an... more Purpose of Review-Premature activation of aging-associated molecular mechanisms is emerging as an important contributor to many diseases, including scleroderma. Among central regulators of the aging process are a group of histone deacetylases called sirtuins (SIRTs). Recent findings implicate these molecules as pathophysiological players in scleroderma skin and lung fibrosis. The goal of this article is to review recent studies on the involvement of SIRTs in scleroderma from the perspective of aging-related molecular mechanisms. Recent Findings-Despite a degree of controversy in this rapidly developing field, the majority of data suggest that SIRT levels are decreased in tissues from patients with scleroderma compared to healthy controls as well as in animal models of scleroderma. Molecular studies reveal several mechanisms through which declining SIRT levels contribute to fibrosis, with the most attention given to modulation of the TGF-β signaling pathway. Activation of SIRTs in cell culture and in animal models elicits antifibrotic effects. Summary-Declining SIRT levels and activity are emerging as pathophysiological contributors to scleroderma. Restoration of SIRTs may be therapeutic in patients with scleroderma.

American Journal of Respiratory Cell and Molecular Biology, Dec 1, 2013

American Journal of Hematology, 2000

Journal of Immunology, Apr 1, 2011

Interleukin (IL)-33 and its receptor ST2 have been recently implicated as critical regulators of ... more Interleukin (IL)-33 and its receptor ST2 have been recently implicated as critical regulators of responses to injury and of ensuing inflammation. The roles of IL-33 and ST2 in pulmonary inflammation and scarring remain unclear. We analyzed bronchoalveolar lavage (BAL) from patients with idiopathic pulmonary fibrosis (IPF), a disease characterized by inflammation, with known elevated levels of IL-8 and excessive collagen deposition in the lungs. IL-33 was not found in BAL from 5 controls but was found in 7 out of 11 IPF samples, at 10.0 ± 3.2 pg/ml. Soluble ST2 was found in BAL from healthy controls at 93.2 ± 82.1 pg/ml, and in all IPF samples at 352.1 ± 135.2 pg/ml (p < 0.05, Mann-Whitney U test). The elevation of IL-33 in BAL suggested that this cytokine may act directly on pulmonary epithelial cells and through this action contribute to inflammation. Cultured human primary pulmonary epithelial cells were stimulated with rhIL-33, and the levels of pro-inflammatory cytokines IL-6, IL-8, MIP-1α, and TNF-α in cell culture media were analyzed by ELISA. Of the analyzed cytokines, only the levels of IL-8 were increased by 2.0 ± 0.2 fold at 24 h and 1.7 ± 0.2 fold at 48 h. In conclusion, levels of IL-33 and ST2 are elevated in the lungs of IPF patients; IL-33 may contribute to inflammation and fibrosis by activating IL-8 production in pulmonary epithelium.

Journal of Immunology, May 1, 2012

Previous reports have been inconsistent on whether Interleukin (IL)-33 necessarily promotes Th2 e... more Previous reports have been inconsistent on whether Interleukin (IL)-33 necessarily promotes Th2 effects in vivo. This diversity of findings may be due to post-synthetic processing of IL-33. We compared the in vivo effects of full-length mouse (flm) and mature mouse (mm) IL-33 utilizing replication-deficient adenovirus (AdV)-mediated gene delivery. mmIL-33 promoted pulmonary eosinophilia, neutrophilia, and significant elevations in IL-4, IL-5, and IL-13 compared to AdV-NULL-infected controls (p < 0.05 in all cases), whereas flmIL-33 had no such effects. A possibility was considered that flmIL-33 may modulate the effects of a prototypic Th2 cytokine, IL-4. The effects of AdV-mediated gene delivery of IL-4 were compared with the effects of combined flmIL-33 and mIL-4. In the latter case, a bicistronic AdV construct encoding flmIL-33 and mIL-4 was used to ensure co-localization of expression of both cytokines. On day 7 after instillation of the viral particles, IL-4-expressing mice had elevated eosinophils and neutrophils in their BAL, and animals expressing both flmIL-33 and IL-4 had yet significantly more BAL eosinophils and neutrophils compared with IL-4-expressing mice (p < 0.05). Similar potentiating effects of flmIL-33 were observed on IL-4-driven increases in pulmonary cytokines TNF-α, IL-5, IL-13, MCP-1, and in goblet cell hyperplasia. These results suggest that although full-length IL-33 has no independent pro-Th2 effect on the lung, it potentiates such effects of IL-4.

Journal of Immunology, Apr 1, 2009

Interstitial lung disease, a combination of pulmonary inflammation and fibrosis, is deadly and oc... more Interstitial lung disease, a combination of pulmonary inflammation and fibrosis, is deadly and occurs idiopathically or as a complication of autoimmune rheumatic diseases (scleroderma, rheumatoid arthritis, poly- and dermatomyositis, lupus). T cells often accumulate in the lungs of such patients. Previous reports suggested that αV-containing integrins may activate TGF-β and facilitate fibrosis. Whether pulmonary T cells utilize such integrins in interstitial lung disease is not clear. Expression of integrins αVβ3 (ITGAVB3) or αVβ5 (ITGAVB5) on pulmonary T cells was observed by double-stain immunofluorescence confocal microscopy in six out of six patients with scleroderma lung disease, as well as in the animal models of pulmonary CCL18 overexpression that manifests in selective T lymphocytic infiltration of the lungs and T cell-dependent pulmonary fibrosis. Flow cytometry of bronchoalveolar lavage T cells confirmed expression of integrins on more than 10% (up to 50%) of pulmonary T cells in 14 of 25 scleroderma patients and in all CCL18-overexpressing mice; Q-PCR experiments confirmed elevated integrin mRNAs in purified BAL T cells. There was no expression of ITGAVB3 or ITGAVB5 on T cells from the lungs of healthy volunteers or control mice. Injections of anti-ITGB3 blocking antibody or genetic deficiency of ITGB3 protected mice from CC18-induced inflammation and fibrosis. Jurkat cells that were forced to overexpress ITGAVB3 or ITGAVB5 induced Smad2 phosphorylation and nuclear translocation, and increases in collagen and α-smooth muscle actin expression in co-cultures with primary lung fibroblasts. Blocking anti-TGF-β antibodies attenuated such regulation in cell co-cultures. Thus, expression of integrins on pulmonary T cells contributes to interstitial lung disease by promoting T cell infiltration, TGF-β activation, and fibrosis.

Journal of Immunology, Apr 1, 2009

We have previously shown that IL-4δ2, a naturally occurring in humans and other species splice va... more We have previously shown that IL-4δ2, a naturally occurring in humans and other species splice variant of IL-4, competes with IL-4 for receptor binding and inhibits some of IL-4 effects on lymphocytes and monocytes. Numerous groups reported that the levels and the ratio of IL-4δ2 and IL-4 mRNAs change in immune, inflammatory, and infectious diseases. It has been suggested that recombinant human (rh) IL-4δ2 can be used therapeutically to neutralize the harmful effects of excess IL-4 in vivo, although it was not clear whether IL-4δ2 mRNA expressing cells secrete IL-4δ2 protein. Transfection of HEK293 or Jurkat cells with IL-4δ2-encoding constructs resulted in IL-4δ2 protein secretion confirmed by LC/MS, ELISA, and Western blotting. To investigate whether IL-4δ2 has no independent activity and acts only as an inhibitor of IL-4, we overexpressed human IL-4δ2 in mouse lungs. Adenovirus-mediated gene delivery of IL-4δ2 caused lymphocytic infiltration similar to that in IL-4-overexpressing mice, as well as proinflammatory/Th1 changes in pulmonary milieu, with the induced levels of TNF-α, IL-1, IFN-γ, IL-12p40, and MCP-1 significantly exceeding those induced by gene delivery of IL-4. Germline deficiency of STAT6 had no effect, whereas deficiency of IL-4Rα significantly attenuated IL-4δ2-induced or IL-4-induced changes in the lungs. Stimulation of primary human T cells or PBMC, but not fibroblasts or A549 cells, with rhIL-4δ2 induced phosphorylation of Jak1, Jak3, and Tyk2, but not of STAT6. IL-4δ2 potently induced production of MCP-1 in human T cells and upregulated IL-4δ2 mRNA production in an autocrine fashion by several hundred fold. Thus, IL-4δ2 is secreted as a protein, acts as a potent autocrine regulator of inflammation and immunity in an IL-4Rα-dependent STAT6-independent fashion, and is a potential novel target for future therapies.

Journal of Immunology, Apr 1, 2011

Activities of T lymphocytes are centrally regulated by interactions between multiple members of t... more Activities of T lymphocytes are centrally regulated by interactions between multiple members of the TNF/TNF-R family. TRAIL is a member of the TNF family with pro-apoptotic activity. The only signaling TRAIL receptor in mice is death receptor (DR) 5. CCL18, a chemokine with selective chemotactic activity on T lymphocytes, is known for its involvement in pulmonary inflammation and fibrosis associated with autoimmune diseases. We measured soluble TRAIL in bronchoalveolar lavage (BAL) fluids. The levels of TRAIL were significantly elevated (p < 0.01, ANOVA) in BAL from 16 patients with scleroderma lung disease (211±110 pg/ml) compared to 16 patients without lung involvement (115±58 pg/ml), or 8 healthy controls (73±41 pg/ml). To determine whether TRAIL is important for CCL18-induced pulmonary infiltration of lymphocytes, recombinant adenovirus-mediated gene delivery of CCL18 was performed in TRAIL KO, DR5 KO, and WT mice. Overexpression of CCL18 caused profound pulmonary lymphocytic infiltration in WT and TRAIL KO mice, compared to control mice infected with AdV-NULL. In contrast, infiltration of T lymphocytes was completely abrogated in CCL18-expressing DR5 KO mice, based on lung histology. Thus, the levels of TRAIL are elevated in the lungs of patients with autoimmunity-associated inflammation and fibrosis, yet TRAIL does not appear to be involved in the CCL18-mediated T lymphocytic infiltration, whereas its receptor DR5 is required for such T cell response to CCL18.

Science Translational Medicine, May 30, 2012

Theoretical Biology and Medical Modelling, Dec 1, 2012

Journal of Leukocyte Biology, Feb 1, 2011

IL-4␦2 is a natural splice variant of IL-4 that lacks the region encoded by the second exon. Nume... more IL-4␦2 is a natural splice variant of IL-4 that lacks the region encoded by the second exon. Numerous reports have suggested that the expression levels of IL-4␦2 change in various diseases, especially those with pulmonary involvement, but the in vivo effects of this splice variant have never been studied. Replication-deficient, AdV-mediated gene delivery of mIL-4␦2 to mouse lungs in vivo was used, and the effects compared with similar adenoviral delivery of mIL-4 or with infection with a noncoding NULL viral construct. Overexpression of IL-4␦2 or IL-4 caused pulmonary infiltration by T and B lymphocytes, whereas in contrast to IL-4, IL-4␦2 did not induce eosinophilia or goblet cell hyperplasia. Microarray analysis of global gene expression revealed that IL-4␦2 and IL-4 had differential effects on gene expression. These splice variants also differentially regulated pulmonary levels of the cytokines TNF-␣, eotaxin, IL-1␣, IFN-␥, and MCP-1, whereas both tended to increase total lung collagen modestly. Pulmonary infiltration by lymphocytes in response to overexpression of IL-4␦2 was attenuated but not abrogated completely by germline deficiency of IL-4R␣ or STAT6, whereas deficiency of endogenous IL-4 had no effect. Thus, IL-4␦2 promotes lymphocytic inflammation in vivo (although differentially from IL-4, in part), and the effects of IL-4␦2 are not mediated by endogenous IL-4. Differential targeting of IL-4␦2 and IL-4 may therefore be considered in developing future therapeutic agents.