Limits...
Counter-regulation of T cell effector function by differentially activated p38.

Alam MS, Gaida MM, Ogawa Y, Kolios AG, Lasitschka F, Ashwell JD - J. Exp. Med. (2014)

Bottom Line: Unlike the MAP kinase (MAPK) cascade that phosphorylates p38 on the activation loop, T cell receptor (TCR) signaling results in phosphorylation on Tyr-323 (pY323, alternative pathway).Notably, UVB treatment of human psoriatic lesions reduced skin-infiltrating p38 pY323(+) T cell IRF4 and IL-17 production.Thus, distinct mechanisms of p38 activation converge on NFATc1 with opposing effects on T cell immunity, which may underlie the beneficial effect of phototherapy on psoriasis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Immune Cell Biology, Center for Cancer Research; Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

ABSTRACT
Unlike the MAP kinase (MAPK) cascade that phosphorylates p38 on the activation loop, T cell receptor (TCR) signaling results in phosphorylation on Tyr-323 (pY323, alternative pathway). Using mice expressing p38α and p38β with Y323F substitutions, we show that alternatively but not MAPK cascade-activated p38 up-regulates the transcription factors NFATc1 and IRF4, which are required for proliferation and cytokine production. Conversely, activation of p38 with UV or osmotic shock mitigated TCR-mediated activation by phosphorylation and cytoplasmic retention of NFATc1. Notably, UVB treatment of human psoriatic lesions reduced skin-infiltrating p38 pY323(+) T cell IRF4 and IL-17 production. Thus, distinct mechanisms of p38 activation converge on NFATc1 with opposing effects on T cell immunity, which may underlie the beneficial effect of phototherapy on psoriasis.

Show MeSH

Related in: MedlinePlus

MAPK-cascade activated p38 inhibits functions distal to alternatively activated p38. (A) Purified CD4+ T cells were cultured overnight without stimulation, and then treated with either UV (50 J/m2 or 100 J/m2 or 200 J/m2), 0.6 M sorbitol for 30 min, or PMA (10 ng/ml) and ionomycin (1 µg/ml) for 1 h. Cell lysates were immunoblotted with anti-phospho-p38. The results are representative of three independent experiments. (B) Purified CD4+ T cells were treated with either 0.6 M sorbitol for 30 min, 50 J/m2 UV, or PMA and ionomycin were stimulated with anti-CD3/CD28 for 24 h. The expression of Nfatc1 and Irf4 was determined by quantitative real-time PCR. Results are the mean ± SEM of three independent experiments. *, P < 0.05 (unpaired two-tailed Student’s t test). (C) Cells were treated as in B, and IRF4 expression was determined by Western blot. The results are representative of two independent experiments. (D) Freshly purified T cells were stimulated or not with anti-CD3/CD28 for 48 h. Cytosolic and nuclear fractions were separated in a low percentage SDS-PAGE (8%) gel and immunoblotted for NFATc1. The results are representative of three independent experiments. (E) CD4+ T cells were stimulated for 48 h with anti-CD3/CD28, and then treated with sorbitol in the presence or absence of SB203580 and/or SP600125 for 30 min, rested for 1 h, then immunoblotted for NFATc1 in cytosolic and nuclear fractions. Results are representative of three independent experiments. (F) Purified CD4+ T cells were treated or not with sorbitol for 30 min and stimulated with anti-CD3/CD28 for 48 h, and then immunoblotted for NFATc1 in cytosolic and nuclear fractions. The results are representative of three independent experiments. (G) Jurkat T cells were stimulated for 48 h with an agonistic anti-TCR antibody (C305), and then treated with sorbitol in the presence or absence of SB203580 and/or SP600125 for 30 min. After 1 h without further stimulation, cytosolic fractions were immunoblotted for phospho-NFATc1 (p-NFATc1). The results are representative of three independent experiments. (H) Recombinant p38 was activated with Zap70, MKK6, or buffer alone in in vitro kinase buffer. After 1 h, recombinant ATF2 and 10 µCi [32P]ATP were added for 30 min before separation on SDS-PAGE and PhosphorImager analysis. The phosphorylation state of p38 Y323 was determined by immunoblotting. The results are representative of three independent experiments. (I) Recombinant p38 was activated with Zap70, MKK6, or buffer alone and an in vitro kinase assay using recombinant NFATc1 as substrate was performed as in (H). The results are representative of two independent experiments. (J) Recombinant p38 was activated with MKK6 or buffer alone in in vitro kinase buffer. Active JNK1 was kept in in vitro kinase buffer. After 1 h, recombinant NFATc1 was added and incubated for an additional hour before separation on SDS-PAGE and immunoblotting with an antibody specific for NFATc1 phosphorylated on residue S172. The results are representative of two independent experiments. (K) Recombinant p38 was activated with Zap70, MKK6, or buffer alone in an in vitro kinase assay with recombinant NFATc1 as the p38 substrate, as in I. Samples were separated on a low percentage SDS-PAGE (8%) and immunoblotted for NFATc1 phosphorylated on residue S172. The results are representative of three independent experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4042639&req=5

fig3: MAPK-cascade activated p38 inhibits functions distal to alternatively activated p38. (A) Purified CD4+ T cells were cultured overnight without stimulation, and then treated with either UV (50 J/m2 or 100 J/m2 or 200 J/m2), 0.6 M sorbitol for 30 min, or PMA (10 ng/ml) and ionomycin (1 µg/ml) for 1 h. Cell lysates were immunoblotted with anti-phospho-p38. The results are representative of three independent experiments. (B) Purified CD4+ T cells were treated with either 0.6 M sorbitol for 30 min, 50 J/m2 UV, or PMA and ionomycin were stimulated with anti-CD3/CD28 for 24 h. The expression of Nfatc1 and Irf4 was determined by quantitative real-time PCR. Results are the mean ± SEM of three independent experiments. *, P < 0.05 (unpaired two-tailed Student’s t test). (C) Cells were treated as in B, and IRF4 expression was determined by Western blot. The results are representative of two independent experiments. (D) Freshly purified T cells were stimulated or not with anti-CD3/CD28 for 48 h. Cytosolic and nuclear fractions were separated in a low percentage SDS-PAGE (8%) gel and immunoblotted for NFATc1. The results are representative of three independent experiments. (E) CD4+ T cells were stimulated for 48 h with anti-CD3/CD28, and then treated with sorbitol in the presence or absence of SB203580 and/or SP600125 for 30 min, rested for 1 h, then immunoblotted for NFATc1 in cytosolic and nuclear fractions. Results are representative of three independent experiments. (F) Purified CD4+ T cells were treated or not with sorbitol for 30 min and stimulated with anti-CD3/CD28 for 48 h, and then immunoblotted for NFATc1 in cytosolic and nuclear fractions. The results are representative of three independent experiments. (G) Jurkat T cells were stimulated for 48 h with an agonistic anti-TCR antibody (C305), and then treated with sorbitol in the presence or absence of SB203580 and/or SP600125 for 30 min. After 1 h without further stimulation, cytosolic fractions were immunoblotted for phospho-NFATc1 (p-NFATc1). The results are representative of three independent experiments. (H) Recombinant p38 was activated with Zap70, MKK6, or buffer alone in in vitro kinase buffer. After 1 h, recombinant ATF2 and 10 µCi [32P]ATP were added for 30 min before separation on SDS-PAGE and PhosphorImager analysis. The phosphorylation state of p38 Y323 was determined by immunoblotting. The results are representative of three independent experiments. (I) Recombinant p38 was activated with Zap70, MKK6, or buffer alone and an in vitro kinase assay using recombinant NFATc1 as substrate was performed as in (H). The results are representative of two independent experiments. (J) Recombinant p38 was activated with MKK6 or buffer alone in in vitro kinase buffer. Active JNK1 was kept in in vitro kinase buffer. After 1 h, recombinant NFATc1 was added and incubated for an additional hour before separation on SDS-PAGE and immunoblotting with an antibody specific for NFATc1 phosphorylated on residue S172. The results are representative of two independent experiments. (K) Recombinant p38 was activated with Zap70, MKK6, or buffer alone in an in vitro kinase assay with recombinant NFATc1 as the p38 substrate, as in I. Samples were separated on a low percentage SDS-PAGE (8%) and immunoblotted for NFATc1 phosphorylated on residue S172. The results are representative of three independent experiments.

Mentions: The existence of a TCR signaling-specific p38 activation pathway raises the possibility that activation of p38 via the otherwise universal mechanism, the MAPK cascade, is ineffective or even detrimental to functional responses, either of which is consistent with the finding that PMA plus ionomycin is a poor inducer of p38-dependent NFATc1 and IRF4 (Fig. 1 E). To ask if classical activation is detrimental, CD4+ T cells were treated with stimuli that initiate the MAPK cascade by different mechanisms to activate p38: sorbitol (osmotic stress), low dose UVB (radiation), and PMA and ionomycin (Fig. 3 A). Whereas none of these stimuli up-regulated NFATc1 or IRF4 mRNA, they inhibited TCR-mediated alternative pathway up-regulation of NFATc1 and IRF4 mRNA (Fig. 3 B) and IRF4 protein (Fig. 3 C). This was not because of toxicity, because these treatments caused little to no reduction in cell viability compared with medium alone (unpublished data). NFAT family members are inactivated by phosphorylation, which results in their retention in the cytosol, and NFATc1 is a known substrate for p38 in vitro and in vivo (Porter et al., 2000). Indeed, in TCR-stimulated primary T cells NFATc1 was found predominantly in the nucleus, where it is active, and the cytosolic fraction migrated more slowly (∼5 kD) when resolved on 8% SDS-PAGE, reflecting its higher degree of phosphorylation (Fig. 3 D). The effect of MAPK cascade-activated p38 on NFATc1 activation was determined by stimulating CD4+ T cells with anti-CD3/CD28 for 48 h to allow up-regulation of NFATc1 expression, and then treatment with medium or sorbitol for 30 min followed by resting the cells for another 1 h. TCR-mediated activation induced accumulation of NFATc1 in the cytosol and the transcriptionally active nuclear fraction (Fig. 3 E). Strikingly, osmotic stress caused egress of NFATc1 from the nucleus to the cytosol, which was largely prevented by addition of the p38 inhibitor SB203580 just before sorbitol treatment. Notably, inhibition of the other major stress kinase, JNK, by SP600125 also prevented the translocation of NFATc1 from the nucleus to the cytosol, and inhibiting both p38 and JNK was additive, resulting the greatest nuclear-to-cytosolic NFATc1 ratio. The effect of MAPK cascade activation on NFATc1 localization was even apparent when the brief sorbitol treatment was performed at the beginning of the 48-h period of activation (Fig. 3 F). In this case, sorbitol caused a reduction in total NFATc1 (compare NFATc1 in the cytosol plus nucleus between sorbitol-treated and -untreated cells), consistent with the reduction seen in NFATc1 mRNA (Fig. 3 B). Notably, almost all of the NFATc1 that was expressed was excluded from the nuclear fraction. Therefore, activation of p38 via the MAPK cascade has acute and long-term effects on the ability TCR-mediated stimulation to induce and activate NFATc1. This raised the possibility that NFATc1, a known p38 substrate (Porter et al., 2000), may be phosphorylated by classically but not alternatively activated p38. Although not mapped in mouse cells, in human cells the phosphorylation of NFATc1 S172 is known to cause cytosolic retention (Chow et al., 2000; Porter et al., 2000). Therefore, we stimulated the human T leukemia cell line Jurkat via the TCR for 48 h, activated the MAPK cascade by treating with sorbitol for 30 min, and, after a 1-h rest, immunoblotted the cytosolic fraction with antibodies specific for phospho-S172 NFATc1 (p-NFATc1; Fig. 3 G). Whereas stimulation via the TCR caused only a small increase in p-NFATc1, sorbitol treatment resulted in high levels. Similar to mouse CD4+ T cells, inhibition of either p38 or JNK reduced the phosphorylation to background levels, and inhibition of both resulted in even lower levels. Consistent with its role in preventing nuclear translocation, p-NFATc1 was undetectable in the nuclear fractions of these cells (unpublished data). Importantly, whereas Zap70-activated p38 (p38 pY323) phosphorylated ATF2 (a substrate common to both classically and alternatively activated p38), as well as MKK6-activated p38 (Fig. 3 H), there was a striking difference in their ability to phosphorylate NFATc1 (Fig. 3 I). NFATc1 S172 is known to be phosphorylated by JNK (Chow et al., 2000). To determine if classically activated p38 can directly target this residue, an in vitro kinase assay using recombinant material was performed. As shown in Fig. 3 J, NFATc1 S172 was phosphorylated by both kinases, consistent with the inhibitor data showing a contribution of both in the retention of NFATc1 in the cytosol. The appearance of phosphorated S172 was accompanied by a shift in the migration of the recombinant NFATc1, another indication of its phosphorylation (Fig. 3 K). Therefore, NFATc1 phosphorylation and inactivation is performed by classically activated but not alternatively activated p38.


Counter-regulation of T cell effector function by differentially activated p38.

Alam MS, Gaida MM, Ogawa Y, Kolios AG, Lasitschka F, Ashwell JD - J. Exp. Med. (2014)

MAPK-cascade activated p38 inhibits functions distal to alternatively activated p38. (A) Purified CD4+ T cells were cultured overnight without stimulation, and then treated with either UV (50 J/m2 or 100 J/m2 or 200 J/m2), 0.6 M sorbitol for 30 min, or PMA (10 ng/ml) and ionomycin (1 µg/ml) for 1 h. Cell lysates were immunoblotted with anti-phospho-p38. The results are representative of three independent experiments. (B) Purified CD4+ T cells were treated with either 0.6 M sorbitol for 30 min, 50 J/m2 UV, or PMA and ionomycin were stimulated with anti-CD3/CD28 for 24 h. The expression of Nfatc1 and Irf4 was determined by quantitative real-time PCR. Results are the mean ± SEM of three independent experiments. *, P < 0.05 (unpaired two-tailed Student’s t test). (C) Cells were treated as in B, and IRF4 expression was determined by Western blot. The results are representative of two independent experiments. (D) Freshly purified T cells were stimulated or not with anti-CD3/CD28 for 48 h. Cytosolic and nuclear fractions were separated in a low percentage SDS-PAGE (8%) gel and immunoblotted for NFATc1. The results are representative of three independent experiments. (E) CD4+ T cells were stimulated for 48 h with anti-CD3/CD28, and then treated with sorbitol in the presence or absence of SB203580 and/or SP600125 for 30 min, rested for 1 h, then immunoblotted for NFATc1 in cytosolic and nuclear fractions. Results are representative of three independent experiments. (F) Purified CD4+ T cells were treated or not with sorbitol for 30 min and stimulated with anti-CD3/CD28 for 48 h, and then immunoblotted for NFATc1 in cytosolic and nuclear fractions. The results are representative of three independent experiments. (G) Jurkat T cells were stimulated for 48 h with an agonistic anti-TCR antibody (C305), and then treated with sorbitol in the presence or absence of SB203580 and/or SP600125 for 30 min. After 1 h without further stimulation, cytosolic fractions were immunoblotted for phospho-NFATc1 (p-NFATc1). The results are representative of three independent experiments. (H) Recombinant p38 was activated with Zap70, MKK6, or buffer alone in in vitro kinase buffer. After 1 h, recombinant ATF2 and 10 µCi [32P]ATP were added for 30 min before separation on SDS-PAGE and PhosphorImager analysis. The phosphorylation state of p38 Y323 was determined by immunoblotting. The results are representative of three independent experiments. (I) Recombinant p38 was activated with Zap70, MKK6, or buffer alone and an in vitro kinase assay using recombinant NFATc1 as substrate was performed as in (H). The results are representative of two independent experiments. (J) Recombinant p38 was activated with MKK6 or buffer alone in in vitro kinase buffer. Active JNK1 was kept in in vitro kinase buffer. After 1 h, recombinant NFATc1 was added and incubated for an additional hour before separation on SDS-PAGE and immunoblotting with an antibody specific for NFATc1 phosphorylated on residue S172. The results are representative of two independent experiments. (K) Recombinant p38 was activated with Zap70, MKK6, or buffer alone in an in vitro kinase assay with recombinant NFATc1 as the p38 substrate, as in I. Samples were separated on a low percentage SDS-PAGE (8%) and immunoblotted for NFATc1 phosphorylated on residue S172. The results are representative of three independent experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4042639&req=5

fig3: MAPK-cascade activated p38 inhibits functions distal to alternatively activated p38. (A) Purified CD4+ T cells were cultured overnight without stimulation, and then treated with either UV (50 J/m2 or 100 J/m2 or 200 J/m2), 0.6 M sorbitol for 30 min, or PMA (10 ng/ml) and ionomycin (1 µg/ml) for 1 h. Cell lysates were immunoblotted with anti-phospho-p38. The results are representative of three independent experiments. (B) Purified CD4+ T cells were treated with either 0.6 M sorbitol for 30 min, 50 J/m2 UV, or PMA and ionomycin were stimulated with anti-CD3/CD28 for 24 h. The expression of Nfatc1 and Irf4 was determined by quantitative real-time PCR. Results are the mean ± SEM of three independent experiments. *, P < 0.05 (unpaired two-tailed Student’s t test). (C) Cells were treated as in B, and IRF4 expression was determined by Western blot. The results are representative of two independent experiments. (D) Freshly purified T cells were stimulated or not with anti-CD3/CD28 for 48 h. Cytosolic and nuclear fractions were separated in a low percentage SDS-PAGE (8%) gel and immunoblotted for NFATc1. The results are representative of three independent experiments. (E) CD4+ T cells were stimulated for 48 h with anti-CD3/CD28, and then treated with sorbitol in the presence or absence of SB203580 and/or SP600125 for 30 min, rested for 1 h, then immunoblotted for NFATc1 in cytosolic and nuclear fractions. Results are representative of three independent experiments. (F) Purified CD4+ T cells were treated or not with sorbitol for 30 min and stimulated with anti-CD3/CD28 for 48 h, and then immunoblotted for NFATc1 in cytosolic and nuclear fractions. The results are representative of three independent experiments. (G) Jurkat T cells were stimulated for 48 h with an agonistic anti-TCR antibody (C305), and then treated with sorbitol in the presence or absence of SB203580 and/or SP600125 for 30 min. After 1 h without further stimulation, cytosolic fractions were immunoblotted for phospho-NFATc1 (p-NFATc1). The results are representative of three independent experiments. (H) Recombinant p38 was activated with Zap70, MKK6, or buffer alone in in vitro kinase buffer. After 1 h, recombinant ATF2 and 10 µCi [32P]ATP were added for 30 min before separation on SDS-PAGE and PhosphorImager analysis. The phosphorylation state of p38 Y323 was determined by immunoblotting. The results are representative of three independent experiments. (I) Recombinant p38 was activated with Zap70, MKK6, or buffer alone and an in vitro kinase assay using recombinant NFATc1 as substrate was performed as in (H). The results are representative of two independent experiments. (J) Recombinant p38 was activated with MKK6 or buffer alone in in vitro kinase buffer. Active JNK1 was kept in in vitro kinase buffer. After 1 h, recombinant NFATc1 was added and incubated for an additional hour before separation on SDS-PAGE and immunoblotting with an antibody specific for NFATc1 phosphorylated on residue S172. The results are representative of two independent experiments. (K) Recombinant p38 was activated with Zap70, MKK6, or buffer alone in an in vitro kinase assay with recombinant NFATc1 as the p38 substrate, as in I. Samples were separated on a low percentage SDS-PAGE (8%) and immunoblotted for NFATc1 phosphorylated on residue S172. The results are representative of three independent experiments.
Mentions: The existence of a TCR signaling-specific p38 activation pathway raises the possibility that activation of p38 via the otherwise universal mechanism, the MAPK cascade, is ineffective or even detrimental to functional responses, either of which is consistent with the finding that PMA plus ionomycin is a poor inducer of p38-dependent NFATc1 and IRF4 (Fig. 1 E). To ask if classical activation is detrimental, CD4+ T cells were treated with stimuli that initiate the MAPK cascade by different mechanisms to activate p38: sorbitol (osmotic stress), low dose UVB (radiation), and PMA and ionomycin (Fig. 3 A). Whereas none of these stimuli up-regulated NFATc1 or IRF4 mRNA, they inhibited TCR-mediated alternative pathway up-regulation of NFATc1 and IRF4 mRNA (Fig. 3 B) and IRF4 protein (Fig. 3 C). This was not because of toxicity, because these treatments caused little to no reduction in cell viability compared with medium alone (unpublished data). NFAT family members are inactivated by phosphorylation, which results in their retention in the cytosol, and NFATc1 is a known substrate for p38 in vitro and in vivo (Porter et al., 2000). Indeed, in TCR-stimulated primary T cells NFATc1 was found predominantly in the nucleus, where it is active, and the cytosolic fraction migrated more slowly (∼5 kD) when resolved on 8% SDS-PAGE, reflecting its higher degree of phosphorylation (Fig. 3 D). The effect of MAPK cascade-activated p38 on NFATc1 activation was determined by stimulating CD4+ T cells with anti-CD3/CD28 for 48 h to allow up-regulation of NFATc1 expression, and then treatment with medium or sorbitol for 30 min followed by resting the cells for another 1 h. TCR-mediated activation induced accumulation of NFATc1 in the cytosol and the transcriptionally active nuclear fraction (Fig. 3 E). Strikingly, osmotic stress caused egress of NFATc1 from the nucleus to the cytosol, which was largely prevented by addition of the p38 inhibitor SB203580 just before sorbitol treatment. Notably, inhibition of the other major stress kinase, JNK, by SP600125 also prevented the translocation of NFATc1 from the nucleus to the cytosol, and inhibiting both p38 and JNK was additive, resulting the greatest nuclear-to-cytosolic NFATc1 ratio. The effect of MAPK cascade activation on NFATc1 localization was even apparent when the brief sorbitol treatment was performed at the beginning of the 48-h period of activation (Fig. 3 F). In this case, sorbitol caused a reduction in total NFATc1 (compare NFATc1 in the cytosol plus nucleus between sorbitol-treated and -untreated cells), consistent with the reduction seen in NFATc1 mRNA (Fig. 3 B). Notably, almost all of the NFATc1 that was expressed was excluded from the nuclear fraction. Therefore, activation of p38 via the MAPK cascade has acute and long-term effects on the ability TCR-mediated stimulation to induce and activate NFATc1. This raised the possibility that NFATc1, a known p38 substrate (Porter et al., 2000), may be phosphorylated by classically but not alternatively activated p38. Although not mapped in mouse cells, in human cells the phosphorylation of NFATc1 S172 is known to cause cytosolic retention (Chow et al., 2000; Porter et al., 2000). Therefore, we stimulated the human T leukemia cell line Jurkat via the TCR for 48 h, activated the MAPK cascade by treating with sorbitol for 30 min, and, after a 1-h rest, immunoblotted the cytosolic fraction with antibodies specific for phospho-S172 NFATc1 (p-NFATc1; Fig. 3 G). Whereas stimulation via the TCR caused only a small increase in p-NFATc1, sorbitol treatment resulted in high levels. Similar to mouse CD4+ T cells, inhibition of either p38 or JNK reduced the phosphorylation to background levels, and inhibition of both resulted in even lower levels. Consistent with its role in preventing nuclear translocation, p-NFATc1 was undetectable in the nuclear fractions of these cells (unpublished data). Importantly, whereas Zap70-activated p38 (p38 pY323) phosphorylated ATF2 (a substrate common to both classically and alternatively activated p38), as well as MKK6-activated p38 (Fig. 3 H), there was a striking difference in their ability to phosphorylate NFATc1 (Fig. 3 I). NFATc1 S172 is known to be phosphorylated by JNK (Chow et al., 2000). To determine if classically activated p38 can directly target this residue, an in vitro kinase assay using recombinant material was performed. As shown in Fig. 3 J, NFATc1 S172 was phosphorylated by both kinases, consistent with the inhibitor data showing a contribution of both in the retention of NFATc1 in the cytosol. The appearance of phosphorated S172 was accompanied by a shift in the migration of the recombinant NFATc1, another indication of its phosphorylation (Fig. 3 K). Therefore, NFATc1 phosphorylation and inactivation is performed by classically activated but not alternatively activated p38.

Bottom Line: Unlike the MAP kinase (MAPK) cascade that phosphorylates p38 on the activation loop, T cell receptor (TCR) signaling results in phosphorylation on Tyr-323 (pY323, alternative pathway).Notably, UVB treatment of human psoriatic lesions reduced skin-infiltrating p38 pY323(+) T cell IRF4 and IL-17 production.Thus, distinct mechanisms of p38 activation converge on NFATc1 with opposing effects on T cell immunity, which may underlie the beneficial effect of phototherapy on psoriasis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Immune Cell Biology, Center for Cancer Research; Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

ABSTRACT
Unlike the MAP kinase (MAPK) cascade that phosphorylates p38 on the activation loop, T cell receptor (TCR) signaling results in phosphorylation on Tyr-323 (pY323, alternative pathway). Using mice expressing p38α and p38β with Y323F substitutions, we show that alternatively but not MAPK cascade-activated p38 up-regulates the transcription factors NFATc1 and IRF4, which are required for proliferation and cytokine production. Conversely, activation of p38 with UV or osmotic shock mitigated TCR-mediated activation by phosphorylation and cytoplasmic retention of NFATc1. Notably, UVB treatment of human psoriatic lesions reduced skin-infiltrating p38 pY323(+) T cell IRF4 and IL-17 production. Thus, distinct mechanisms of p38 activation converge on NFATc1 with opposing effects on T cell immunity, which may underlie the beneficial effect of phototherapy on psoriasis.

Show MeSH
Related in: MedlinePlus