Staphylococcus aureus membrane and diacylated lipopeptide induce thymic stromal lymphopoietin in keratinocytes through the Toll-like receptor 2–Toll-like.

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Presentation transcript:

Staphylococcus aureus membrane and diacylated lipopeptide induce thymic stromal lymphopoietin in keratinocytes through the Toll-like receptor 2–Toll-like receptor 6 pathway Anh Tuan Vu, MD, PhD, Tadashi Baba, PhD, Xue Chen, MD, Tuan Anh Le, MD, PhD, Hirokazu Kinoshita, MD, PhD, Yang Xie, MD, Seiji Kamijo, PhD, Keiichi Hiramatsu, MD, PhD, Shigaku Ikeda, MD, PhD, Hideoki Ogawa, MD, PhD, Ko Okumura, MD, PhD, Toshiro Takai, PhD Journal of Allergy and Clinical Immunology Volume 126, Issue 5, Pages 985-993.e3 (November 2010) DOI: 10.1016/j.jaci.2010.09.002 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 FSL-1 induced the release of TSLP in keratinocytes. Keratinocytes were stimulated with PGN (20 μg/mL), triacylated lipopeptide (Pam3CSK4, 5 μg/mL), or diacylated lipopeptide (FSL-1, 1 μg/mL). A, TSLP. B, IL-8. Broken line, Minimum detection limit. Data shown are the means ± SDs for 3 wells and are representative of 3 independent experiments with similar results. ∗P < .001 versus the medium by means of ANOVA with the Tukey multiple comparison test. Journal of Allergy and Clinical Immunology 2010 126, 985-993.e3DOI: (10.1016/j.jaci.2010.09.002) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 FSL-1 induced upregulation of the expression of TSLP and other proinflammatory molecules in keratinocytes. A, Levels of mRNA are presented relative to the medium at 4 hours. B, Protein concentrations in the culture supernatant. Data shown are the values for single wells (Fig 2, A) and means ± SDs for 3 wells (Fig 2, B) and are representative of 3 independent experiments with similar results. ∗P < .05 versus the medium and #P < .05 versus Pam3CSK4 by means of ANOVA with the Tukey multiple comparison test (Fig 2, B). Levels of cytokines (TSLP, TNF-α, IL-6, and GM-CSF), chemokines (CCL2/monocyte chemoattractant protein 1 [MCP-1], CCL5/RANTES, CCL20/macrophage inflammatory protein 3α [MIP-3α], CCL27/cutaneous T cell–attracting chemokine [CTACK], CXCL8/IL-8, and CXCL10/IFN-inducible protein 10 [IP-10]), and an adhesion molecule (CD54/intercellular adhesion molecule 1 [ICAM-1]) were measured. Journal of Allergy and Clinical Immunology 2010 126, 985-993.e3DOI: (10.1016/j.jaci.2010.09.002) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Knockdown of TLR2 and TLR6 inhibited the FSL-1–induced TSLP mRNA expression in keratinocytes. A and B, Keratinocytes transfected with siRNAs by using lipofectamine2000 (LA2000) were stimulated with FSL-1 (1 μg/mL). L and M, Thirty-five percent to 45% and 45% to 55% guanine-cytosine content, respectively. TLR1-siRNA1, TLR2-siRNA3, and TLR6-siRNA3 were used. Data shown are the values for single wells and representative of 3 independent experiments with similar results. Journal of Allergy and Clinical Immunology 2010 126, 985-993.e3DOI: (10.1016/j.jaci.2010.09.002) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 TH2 cytokines and TNF-α upregulated the FSL-1–induced release of TSLP in keratinocytes. A, TSLP. B, IL-8. Broken line, Minimum detection limit. Data shown are the means ± SD for 3 wells and representative of 3 independent experiments with similar results. ∗P < .001 versus without FSL-1 and #P < .001 versus without TH2/TNF-α by means of ANOVA with the Tukey multiple comparison test. Journal of Allergy and Clinical Immunology 2010 126, 985-993.e3DOI: (10.1016/j.jaci.2010.09.002) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 S aureus membranous fraction induced an upregulation of the gene expression of TSLP in a manner dependent on the expression of TLR2 and TLR6 in keratinocytes. A, Dose dependency. B and C, Keratinocytes transfected with siRNAs were stimulated with the membranous fraction of the S aureus MW2 strain (1.7 U/mL). L and M, Thirty-five percent to 45% and 45% to 55% guanine-cytosine content, respectively. TLR1-siRNA1, TLR2-siRNA3, and TLR6-siRNA2 were used. Data shown are the values for single wells (Fig 5, A) or the means ± SDs for 3 wells (Fig 5, B and C) and are representative of 3 independent experiments with similar results. ∗P < .05, ∗∗P < .01, and #P < .001 versus the control siRNA by means of ANOVA with the Tukey multiple comparison test (Fig 5, B and C). D, mRNA expression of TLRs relative to the average of TLR6 expression. Data shown are the means ± SDs for 5 independent experiments. ∗P < .05 and ∗∗P < .01 by using the Mann-Whitney U test (2-tailed). Journal of Allergy and Clinical Immunology 2010 126, 985-993.e3DOI: (10.1016/j.jaci.2010.09.002) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 S aureus membranous fraction induced release of TSLP in keratinocytes. Keratinocytes were induced to differentiate by culturing with FBS before stimulation. A and B, Release of TSLP and IL-8 on stimulation with the subcellular fractions of the S aureus MW2 strain. C and D, Dose dependency of the release of TSLP (Fig 6, C) and IL-8 (Fig 6, D) by the S aureus membranous fraction, FSL-1, Pam3CSK4, and polyI:C. Broken line, Minimum detection limit. Data shown are the values for single wells (Fig 6, A and B) or the means ± SDs for 3 wells (Fig 6, C and D) and are representative of 3 independent experiments with similar results. Journal of Allergy and Clinical Immunology 2010 126, 985-993.e3DOI: (10.1016/j.jaci.2010.09.002) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Effect of cytokines on S aureus membrane– and FSL-1–induced release of TSLP in keratinocytes. Keratinocytes were induced to differentiate by culturing with FBS before stimulation. Release of TSLP (A) and IL-8 (B) on stimulation with the membranous fraction of the S aureus MW2 strain was measured. Broken line, Minimum detection limit. Data shown are the means ± SDs for 3 wells and representative of 3 independent experiments with similar results. ∗P < .05 versus the medium by means of ANOVA with the Newman-Keuls multiple comparison test. Journal of Allergy and Clinical Immunology 2010 126, 985-993.e3DOI: (10.1016/j.jaci.2010.09.002) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 8 Heat-killed bacterial whole cells of S aureus strains isolated from patients with AD induced release of TSLP in keratinocytes. Keratinocytes were induced to differentiate by culturing with FBS before stimulation. Release of TSLP (A) and IL-8 (B) on stimulation with the heat-killed S aureus cells of the MW2 strain and 2 strains isolated from patients with AD (D-YSD1 and D-ISK1). Broken line, Minimum detection limit. Data shown are the means ± SDs for 3 wells and representative of 3 independent experiments with similar results. ∗P < .05 versus the medium and #P < .05 versus without TNF-α by means of ANOVA with the Newman-Keuls multiple comparison test. Journal of Allergy and Clinical Immunology 2010 126, 985-993.e3DOI: (10.1016/j.jaci.2010.09.002) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Knockdown of TLR2 and TLR6 inhibited S aureus membrane–induced upregulation of TSLP mRNA expression in keratinocytes. In Fig 5, B and C, the level of TLR1 mRNA after stimulation with the membranous fraction was suppressed by means of TLR1 siRNA compared with the control siRNA with the low guanine-cytosine content but was higher than that seen in unstimulated keratinocytes (Fig 5, B, TLR1 mRNA). Therefore results obtained in another experiment, in which the level of TLR1 mRNA in keratinocytes transfected with TLR1 siRNA was lower after stimulation than in the unstimulated keratinocytes, are shown here. Relatively little inhibition of the upregulation of TSLP gene expression by TLR1 siRNA (32% reduction) compared with that by TLR2 and TLR6 siRNAs (88% and 72% reduction respectively) was observed (Fig E1, B), suggesting that the S aureus membranous fraction induces TSLP in keratinocytes through the TLR2-TLR6 pathway similarly to that seen in Fig 5, B and C. Keratinocytes transfected with siRNAs using Lipofectamine2000 (LA2000) were stimulated with S aureus membrane (1.7 U/mL). L and M, Thirty-five percent to 45% and 45% to 55% guanine-cytosine content, respectively. TLR1-siRNA1, TLR2-siRNA3, and TLR6-siRNA2 were used. Journal of Allergy and Clinical Immunology 2010 126, 985-993.e3DOI: (10.1016/j.jaci.2010.09.002) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Vicious cycles between colonization with S aureus and AD and modulation by cytokine milieu. A, Vicious cycles between colonization by S aureus and AD. S aureus–derived TLR2-TLR6 ligands and extracellular proteases promote AD. In turn, the inflammatory TH2 (TH2/TNF) cytokine milieu in patients with AD further promotes the S aureus colonization. B, The cytokine milieu modulates the vicious cycles. For further information, see the Discussion section. Journal of Allergy and Clinical Immunology 2010 126, 985-993.e3DOI: (10.1016/j.jaci.2010.09.002) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions