Involvement of p38 mitogen-activated protein kinase in heat shock protein 27 induction in human neutrophils

Niwa, Masayuki; Hotta, Koichi; Kanamori, Yutaka; Hatakeyama, Daijiro; Hirade, Kouseki; Katayama, Masaki; Hara, Akira; Mori, Hideki; Ito, Hidenori; Kato, Kanefusa; Matsuno, Hiroyuki; Kozawa, Osamu

doi:10.1016/s0014-2999(03)01571-1

Cited by 16 publications

(12 citation statements)

References 28 publications

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“…A number of candidate molecules exist including heat shock protein 27 (hsp27) that regulates actin assembly and leukocyte specific protein 1 (LSP1), an F-actin binding protein that is a major substrate of the p38 downstream kinase, MAPK-activated protein kinase 2 [31,32]. Taken together with data from the current study, inhibition of p38 MAPK prevents cytoskeletal rearrangements potentially by inhibition of downstream effector proteins such as hsp27 which is present in neutrophils [33] and endothelial cells [34] or LSP1 which has been identified in neutrophils [31,35]. Finally, inhibition of p38 MAPK decreased neutrophil influx and protein leak into the lungs during acute lung injury in this in vivo model which may therefore have an important therapeutic role in ARDS.…”

Section: Discussionmentioning

confidence: 52%

Blockade of p38 map kinase inhibits complement-induced acute lung injury in a murine model

Nash

Heuertz

2005

International Immunopharmacology

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Section: Discussionmentioning

confidence: 52%

Blockade of p38 map kinase inhibits complement-induced acute lung injury in a murine model

Nash

Heuertz

2005

International Immunopharmacology

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“…In addition, recent studies have shown that TNF␣ is expressed in both CD34 ϩ hematopoietic cells and in human erythroid progenitors at colony-forming unit erythroid E stages of differentiation (44). Moreover, it has been demonstrated that, in neutrophils, Hsp27 protein expression is directly regulated by TNF␣ (45). These observations lead us to determine whether TNF␣ is expressed during late stages of differentiation.…”

Section: Discussionmentioning

confidence: 97%

Differentiation stage-specific activation of p38 mitogen-activated protein kinase isoforms in primary human erythroid cells

Uddin

Ah-Kang

Ulaszek

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

146

110

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p38␣, p38␤, p38␥, and p38␦ are four isoforms of p38 mitogenactivated protein (MAP) kinase (MAPK) involved in multiple cellular functions such as cell proliferation, differentiation, apoptosis, and inflammation response. In the present study, we examined the mRNA expression pattern of each of the four isoforms during erythroid differentiation of primary erythroid progenitors. We show that p38␣ and p38␥ transcripts are expressed in early hematopoietic progenitors as well as in late differentiating erythroblasts, whereas p38␦ mRNA is only expressed and active during the terminal phase of erythroid differentiation. On the other hand, p38␤ is minimally expressed in early CD34 ؉ hematopoietic progenitors but not expressed in lineage-committed erythroid progenitors. We also determined the phosphorylation͞activation of p38␣, MAPK kinase 3͞6, and MAPKAP-2 in response to erythropoietin and stem cell factor. We found that phosphorylation of p38␣, MAPK kinase kinase 3͞6 and MAPKAP-2 occurs only upon growth factor withdrawal in primary erythroid progenitors. Moreover, our data indicate that activation of p38␣ does not induce apoptosis or promote proliferation of erythroid progenitors. On the other hand, under steady-state culture conditions, both p38␣ and p38␦ isoforms are increasingly phosphorylated activated in the terminal phase of differentiation. This increased phosphorylation͞ activity was accompanied by up-regulation of heat shock protein 27 phosphorylation. Finally, we demonstrate that tumor necrosis factor ␣, an inflammatory cytokine that is modulated by p38␣, is expressed by differentiating erythroblasts and inhibition of p38␣ or tumor necrosis factor ␣ results in reduction in differentiation. Taken together, our data demonstrate that both p38␣ and ␦ isoforms function to promote the late-stage differentiation of primary erythroid progenitors and are likely to be involved in functions related to erythrocyte membrane remodeling and enucleation.

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“…28,29 The enhancement of the downregulation of Hsp27, Mcl-1 and Bcl-X L proteins by p38 inhibition with various apoptotic agents has been previously shown in other cell types and is likely due to various mechanisms. [29][30][31] Inhibiting p38 with SCIO-469 reduces Hsp27 phosphorylation (Figure 1b) but inhibiting Hsp27 phosphorylation alone may not be sufficient to induce MM cytotoxicity (Figures 4 and 5). However, SCIO-469 may diminish Hsp27 levels as a direct consequence of inhibiting Hsp27 phosphorylation in MM cells, as reported in neutrophils.…”

Section: Discussionmentioning

confidence: 99%

“…However, SCIO-469 may diminish Hsp27 levels as a direct consequence of inhibiting Hsp27 phosphorylation in MM cells, as reported in neutrophils. 30 Also, it has been shown in human keratinocytes that UVA treatment results in the activation of p38 which is required to maintain the stability of Bcl-X L after DNA damage. 29 Bortezomib induces p38 activity in MM cells 7 and p38 may be similarly required to maintain the stability of Bcl-X L in response to bortezomib.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of p38α MAPK enhances proteasome inhibitor-induced apoptosis of myeloma cells by modulating Hsp27, Bcl-XL, Mcl-1 and p53 levels in vitro and inhibits tumor growth in vivo

Navas¹,

Nguyen²,

Hideshima

et al. 2006

Leukemia

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Inhibition of p38 kinase blocks the production of tumorpromoting factors in the multiple myeloma (MM) bone marrow microenvironment. Proteasome inhibitors MG132 and bortezomib have been shown to have direct cytotoxic effects on MM cells. We show that a selective inhibitor of p38a, SCIO-469, enhances the ability of MG132 and bortezomib to induce the apoptosis of MM cells. Previously, we showed that p38 inhibition with SCIO-469 enhances MM cytotoxicity of bortezomib by inhibiting the transient expression and phosphorylation of Hsp27, a downstream target of p38. Here we show that continued treatment of MM cells with bortezomib leads to a SCIO-469-enhanced downregulation of Hsp27 and to increased MM apoptosis. Furthermore, we show that p38 inhibition enhances the bortezomib-induced MM apoptosis by upregulation of p53 and downregulation of Bcl-X L and Mcl-1. In a mouse xenograft plasmacytoma model of MM, we found that inhibiting p38 augments the effects of bortezomib in decreasing MM tumor growth in vivo. Thus, in addition to its role in suppressing an activated MM microenvironment, co-treatment with a p38 inhibitor, such as SCIO-469, may enhance the cytotoxicity of bortezomib by modulating pro-apoptotic and anti-apoptotic factors in MM cells, suggesting great potential for co-therapy.

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Involvement of p38 mitogen-activated protein kinase in heat shock protein 27 induction in human neutrophils

Cited by 16 publications

References 28 publications

Blockade of p38 map kinase inhibits complement-induced acute lung injury in a murine model

Blockade of p38 map kinase inhibits complement-induced acute lung injury in a murine model

Differentiation stage-specific activation of p38 mitogen-activated protein kinase isoforms in primary human erythroid cells

Inhibition of p38α MAPK enhances proteasome inhibitor-induced apoptosis of myeloma cells by modulating Hsp27, Bcl-XL, Mcl-1 and p53 levels in vitro and inhibits tumor growth in vivo

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