T Cell Proliferation in Response to Interleukins 2 and 7 Requires p38MAP Kinase Activation

Although it is well appreciated that arachidonic acid, a second messenger molecule that is released by ligandstimulated phospholipase A 2 , stimulates a wide range of cell types, the mechanisms that mediate the actions of arachidonic acid are still poorly understood. We now report that arachidonic acid stimulated the appearance of dual-phosphorylated (active) p38 mitogen-activated protein kinase as detected by Western blotting in HeLa cells, HL60 cells, human neutrophils, and human umbilical vein endothelial cells but not Jurkat cells. An increase in p38 kinase activity caused by arachidonic acid was also observed. Further studies with neutrophils show that the stimulation of p38 dual phosphorylation by arachidonic acid was transient, peaking at 5 min, and was concentration-dependent. The effect of arachidonic acid was not affected by either nordihydroguaiaretic acid, an inhibitor of the 5-, 12-, and 15-lipoxygenases or by indomethacin, an inhibitor of cyclooxygenase. Arachidonic acid also stimulated the phosphorylation and/or activity of the extracellular signal-regulated protein kinase and of c-jun N-terminal kinase in a cell-typespecific manner. An examination of the mechanisms through which arachidonic acid stimulated the phosphorylation/activity of p38 and extracellular signal-regulated protein kinase in neutrophils revealed an involvement of protein kinase C. Thus, arachidonic acid stimulated the translocation of protein kinase C ␣, ␤I, and ␤II to a particulate fraction, and the effects of arachidonic acid on mitogen-activated protein kinase phosphorylation/activity were partially inhibited by GF109203X, an inhibitor of protein kinase C. This study is the first to demonstrate that a polyunsaturated fatty acid causes the dual phosphorylation and activation of p38.

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“…1). In contrast to the above data, 20:4 6 did not enhance p38 dual phosphorylation in Jurkat cells (data not shown) that express p38 (26).…”

Section: Resultscontrasting

confidence: 52%

Stimulation of p38 Phosphorylation and Activity by Arachidonic Acid in HeLa Cells, HL60 Promyelocytic Leukemic Cells, and Human Neutrophils

Hii¹,

Huang²,

Bilney³

et al. 1998

Journal of Biological Chemistry

100

101

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“…One such compound, SB203580, blocks the activity of p38␣ and p38␤, but does not inhibit p38␥ and p38␦ (23), nor the extracellular signal-related kinases or c-Jun N-terminal kinases (24,25). It has been reported that the production of IFN-␥ by T cells, following activation by specific Ag-pulsed APC, is mediated by the p38 MAPK signaling pathway (26).…”

Section: Discussionmentioning

confidence: 99%

Enhanced Secretion of IFN-γ by Activated Th1 Cells Occurs Via Reverse Signaling Through TNF-Related Activation-Induced Cytokine

Chen¹,

Huang²,

Hsieh³

2001

The Journal of Immunology

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Growing evidence has demonstrated that members of TNF superfamily transduce signals after engagement with their receptors. TNF-related activation-induced cytokine (TRANCE), a member of TNF superfamily, is preferentially expressed on the surface of activated CD4+ Th1 cells. The soluble receptor activator of NF-κB (RANK).Fc fusion protein suppresses IFN-γ secretion by activated Th1 cells, but does not affect IL-4 secretion by Th2 cells. The suppressive effect on IFN-γ secretion is observed when Th1 cells are activated by APCs, but not by immobilized anti-TCRβ mAb. In contrast, immobilized RANK.Fc fusion protein augments IFN-γ secretion by Th1 cells, indicating the occurrence of reverse signaling through TRANCE during T cell/APC interaction. The enhanced secretion of IFN-γ mediated via TRANCE correlates with the activation of p38 mitogen-activated protein kinase and is blocked by SB203580, a p38 mitogen-activated protein kinase-specific inhibitor. Thus, in addition to its role in activating dendritic cells by binding to the receptor RANK, TRANCE itself can signal the augmentation of IFN-γ secretion via a p38-dependent pathway, and this provides yet another example of reverse signaling by a member of TNF superfamily.

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“…Meanwhile, in the mesenteric lymph nodes, where pre-matured T cells expand and mature into cytotoxic T cells, donor-derived CD8 + and CD4 + lymphocytes are fewer in p38a +/--grafted mice. Several studies have reported that activated p38 up-regulates the expression of several cytokines, such as IL-12p40, IL-18, and IL-4 [16,17,27], and plays essential roles in T cell proliferation in vitro and in vivo [18][19][20]. The induction of Th1-dominant cytokines, such as IL-12p40 and IL-18, was suppressed in the MLNL of p38a +/--grafted mice, which may be one of the reasons why fewer lymphocytes infiltrated into the MLNL.…”

Section: Discussionmentioning

confidence: 99%

“…Among the four mammalian isoforms of p38 (p38a, -b, -c, and -d), p38a is expressed relatively ubiquitously [10][11][12], and p38a-deficient mice have been reported to be homozygous embryonic lethal due to either abnormal erythropoiesis or placental organogenesis [13]. The p38 plays a pivotal role in Th1/Th2 responses by regulating the expression of cytokines, such as IL-2, IL-4, IL-12, and IFN-c [14][15][16][17], and also plays important roles in modulating proliferation and cell death [18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Reduced p38 mitogen-activated protein kinase in donor grafts accelerates acute intestinal graft-versus-host disease in mice

et al. 2005

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The gastrointestinal tract is a major target of graft-versus-host disease (GVHD), which constitutes a life-threatening complication of bone marrow transplantation. GVHD is mainly caused by the activation of donor-derived lymphocytes, in which cytokine cascades play essential roles. Since p38 MAPK (p38) has been identified as a regulator of cytokine reactions and proposed as a molecular target for anti-inflammatory therapy, we investigated the contribution of p38 to the severity of murine intestinal GVHD. Unexpectedly, p38a +/-donor graft induced more acute GVHD-related mortality and more severe gut injury. The survival of p38a +/-donor-derived intestinal intraepithelial lymphocytes (IEL) was prolonged in vitro and in vivo, and TNF-a expression in the p38a +/-donor-derived IEL was also increased compared with wild-type cells. In contrast, the p38a +/-grafted mice resulted in decreased expansion of donor lymphocytes in mesenteric lymph nodes, and the up-regulation of IL-12p40 and IL-18 was diminished. These findings suggest that p38 has dichotomous effects for inflammatory response in vivo; not only regulates inflammatory cytokine expression and lymphocyte expansion, but also has distinct regulatory functions for IEL in intestinal GVHD. In conclusion, the inhibition of p38 may not be a suitable antiinflammatory strategy for GVHD due to the associated intestinal injury.

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T Cell Proliferation in Response to Interleukins 2 and 7 Requires p38MAP Kinase Activation

Cited by 231 publications

References 64 publications

Stimulation of p38 Phosphorylation and Activity by Arachidonic Acid in HeLa Cells, HL60 Promyelocytic Leukemic Cells, and Human Neutrophils

Stimulation of p38 Phosphorylation and Activity by Arachidonic Acid in HeLa Cells, HL60 Promyelocytic Leukemic Cells, and Human Neutrophils

Enhanced Secretion of IFN-γ by Activated Th1 Cells Occurs Via Reverse Signaling Through TNF-Related Activation-Induced Cytokine

Reduced p38 mitogen-activated protein kinase in donor grafts accelerates acute intestinal graft-versus-host disease in mice

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