||Investigating the Pathogenesis in Chemically Induced IFN-γ-mediated Skin Inflammation
||Institute of Clinical Medicine
Glycogen synthase kinase-3
Macrophage migration inhibitor factor
Natural killer T
CXC chemokine receptor 2
皮膚提供最大的免疫屏障。異常的皮膚免疫反應導致多種發炎性皮膚疾病，包含乾癬、接觸性皮膚炎、濕疹，等其他皮膚炎。為了研究皮膚炎的治療策略，我們使用豆蔻酰佛波醇乙酯 (TPA) 誘導實驗性的類乾癬皮膚發炎徵狀。皮膚組織丙型干擾素 (IFN-γ) 的過度表現被推測是乾癬疾病的進程主因。由於肝醣合成酶激酶-3 (GSK-3) 能促進丙型干擾素訊息傳遞，然而肝醣合成酶激酶-3在皮膚發炎的角色仍然不清楚。本論文中，實驗證明小鼠丙型干擾素受體1 (IFNGR1) 的缺乏可削弱TPA誘導急性和慢性皮膚發炎反應，包含小鼠耳朵增厚、真皮層白血球與顆粒性白血球的發炎浸潤、細胞間黏附因子1 (CD54) 的表現、表皮層過度增生以及真皮層血管新生作用，卻不影響CD3 T細胞的浸潤作用。為了釐清肝醣合成酶激酶-3於丙型干擾素媒介皮膚炎症的致病角色，透過藥物靛玉紅衍生物 (BIO) 處理或慢病毒攜帶shRNA干擾子轉殖方法進而抑制肝醣合成酶激酶-3皆能夠降低皮膚發炎反應，但仍不影響CD3 T細胞的浸潤作用。抑制肝醣合成酶激酶-3能有效地減少CD3 T細胞表現丙型干擾素係透過減少T細胞轉錄因子 (T-bet) 入核調控丙型干擾素訊息RNA轉錄表現。過去研究證實巨噬細胞移動抑制因子 (MIF) 可直接趨化CD3 T細胞的移行作用，但是巨噬細胞移動抑制因子是否媒介丙型干擾素產生細胞之趨化作用仍是未知的。巨噬細胞移動抑制因子的釋放經常是伴隨著細胞傷害致使細胞通透增加之後，所以我們偵測被豆蔻酰佛波醇乙酯刺激的小鼠耳朵和人類角質細胞株HaCaT的巨噬細胞移動抑制因子釋放程度。結果指出豆蔻酰佛波醇乙酯直接地造成的細胞毒殺作用會伴隨著巨噬細胞移動抑制因子釋放。以巨噬細胞移動抑制因子拮抗藥物 (ISO-1) 治療能有效地降低豆蔻酰佛波醇乙酯誘發的小鼠耳朵增厚、白血球浸潤、表皮層細胞增生和真皮層血管新生作用。重要的是阻斷巨噬細胞移動因子能有效地減少表現丙型干擾素之自然殺手T細胞於皮膚真皮層的浸潤；豆蔻酰佛波醇乙酯和巨噬細胞移動抑制因子分別地刺激自然殺手T細胞表現丙型干擾素產生和促進移轉作用。研究顯示巨噬細胞移動抑制因子係透過胞膜CD74和化學趨化受體CXCR2共同調控CD44/CD74/CXCR2/CXCR4/CD56bright/CD3自然殺手T細胞的趨化作用；而且，自然殺手細胞的剔除結果抑制了豆蔻酰佛波醇乙酯誘發的皮膚炎症。在豆蔻酰佛波醇乙酯誘導皮膚發炎模式下，巨噬細胞抑制因子是從受傷害的角質細胞釋放的，接著誘導具有CD74和CXCR2表現且能產生丙型干擾素的自然殺手T細胞趨化移轉。除此之外，肝醣合成酶激酶-3活化也可能調節自然殺手T細胞的丙型干擾素產生抑或是調控丙型干擾素訊息傳遞進而促使丙型干擾素所媒介的皮膚炎症病程發展。本研究證實標靶於巨噬細胞抑制因子和肝醣合成酶激酶-3可將運用於皮膚炎症的潛在性治療策略。
Skin provides the largest immunity barrier. Abnormal immune responses in skin result in a large variety of inflammatory skin diseases, including psoriasis, contact dermatitis, eczema, and others. To investigate the therapeutic strategies of dermatitis, we used the 12-O-tetradecanoylphorbol-13-acetate (TPA) to induce an experimental model of psoriasis-like skin inflammation. Overexpression of interferon (IFN)-γ in skin is considered a major contributor of psoriatic progression. The role of glycogen sythase kinase (GSK)-3, which facilitates IFN-γ signaling pathway, is still unclear in skin inflammation. We firstly confirmed IFN-γ receptor 1 deficiency attenuated the acute and chronic skin inflammatory responses in mice, including ear swelling, the dermal inflammatory infiltration of leucocytes and granuocytes, the expression of intercellular adhesion molecule 1 (CD54), epidermal hypoperliferation, and dermal angiogenesis, but not affected the infiltration of CD3+ cells. To verify the pathogenic role of GSK-3 in IFN-γ-mediated skin inflammation, inhibiting GSK-3 pharmacologically by administering to 6-bromoindirubin-3’-oxime and genetically with lentiviral-based short-hairpin RNA decreased skin inflammatory responses but still not affected the infiltration of CD3+ cells. Notably, inhibiting GSK-3 reduced the IFN-γ production and the nuclear translocation of T-box transcription factor Tbx21, a transcription factor of IFN-γ expression, in CD3+ cells. Regarding Macrophage migration inhibitory factor (MIF) may directly trigger the migration of CD3+ T cells, it is still unknown whether MIF triggers an initial step for the chemotaxis of IFN-γ-producing cells in TPA-induced skin inflammation. The release of MIF can be observed usually accompanied by the cell damage; therefore, we measured the release level of MIF in TPA-challenged mice ear and human keratinocytic HaCaT cells. The results indicated TPA directly caused cytotoxicity which leading to MIF release concurrently. Treatment with the MIF antagonist (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester, ISO-1, considerably attenuated TPA-induced ear swelling, leukocyte infiltration, epidermal cell proliferation, and dermal angiogenesis. Blocking MIF greatly diminished the dermal infiltration of murine IFN-γ+ natural killer (mNK) T cells as well as mNKT cells. Administering exogenous TPA and MIF promoted IFN-γ production and migration respectively particularly in NKT cells. MIF specifically triggered the chemotaxis of human CD44+CD74+CXCR2+CXCR4+CD56brightCD3+ (hNKT) cells via CD74 and CXCR2; furthermore, the depletion of NK1.1 positive cells abolished the TPA-induced skin inflammation. For TPA-induced skin inflammation, MIF is released from damaged keratinocytes and then triggers the chemotaxis of CD74+CXCR2+ mNKT cells for IFN-γ production. In these cells, GSK-3 activation possibly mediates not only the IFN-γ production in NKT cells but IFN-γ signaling pathway in targeting cells to facilitate IFN-γ-mediated skin disease progression. These findings suggest that targeting MIF and GSK-3 may be the potential therapeutic strategies against skin inflammation.
Abstract in English I
Abstract in Chinese III
Table List IX
Figure List IX
Appendix List X
Chapter 1 Introduction 1
1-1 Skin immune surveillance 1
1-2 Psoriasis 2
1-3 12-O-tetradecanoylphorbol-13-acetate-induced psoriasis-like skin inflammation 3
1-4 IFN-γ signaling pathway 4
1-5 Glycogen synthase kinase-3 5
1-6 Macrophage migration inhibitory factor 6
1-7 Natural killer T cells in skin disorders 7
Chapter 2 Objectives and Specific Aims 10
Chapter 3 Materials and Methods 12
3-1 Drugs and reagents 12
3-2 Acute and chronic models of TPA-induced skin inflammation 13
3-3 Cell culture 14
3-4 TPA stimulation of human keratinocytes in vitro 15
3-5 Analysis of cytotoxicity and apoptosis 15
3-6 H&E staining 16
3-7 Immunostaining 16
3-8 Enzyme-linked immunosorbent assay 18
3-9 Short hairpin RNA transfection in vitro and in vivo 18
3-10 Western blot analysis 19
3-11 Luciferase reporter assay 20
3-12 Separation of human and mouse peripheral blood mononuclear cells 20
3-13 Isolation of human CD56+CD3+ (hNKT), CD56+CD3- (hNK), and murine CD3+NK1.1+ (mNKT) cells 21
3-14 The cellular marker magnetic isolation 22
3-15 Surface marker analysis 23
3-16 Stimulation of primary human blood cells 24
3-17 Transmigration assay 25
3-18 Depletion of granulocyte and NK1.1+ cells 26
3-19 Treatment of MIF antagonist ISO-1 26
3-20 Image quantification 26
3-21 Statistical analyses 28
Chapter 4 Results 29
4-1 IFNGR1 is required for TPA-induced acute skin inflammation 29
4-2 TPA activates GSK-3 and induces GSK-3-regulated IFN-γ signaling 29
4-3 GSK-3 facilitates TPA-induced acute skin inflammatory responses 30
4-4 GSK-3 facilitates TPA-induced ear swelling and granulocyte infiltration 31
4-5 GSK-3 facilitates TPA-induced IFN-γ production in CD3-positive cells by regulating T-bet nuclear translocation 31
4-6 GSK-3 facilitates IFN-γ-mediated chronic TPA-induced psoriasis-like cutaneous inflammation 32
4-7 TPA stimulation directly causes MIF release and cytotoxicity in keratinocytes in vivo and in vitro 32
4-8 The MIF antagonist ISO-1 attenuates TPA-induced acute and chronic skin inflammation in mouse ears 33
4-9 The pharmacological inhibition of MIF reduces the TPA-induced infiltration of dermal IFN-γ+ mNKT cells 35
4-10 TPA, but not MIF, induces IFN-γ production in CD56+CD3+ hNKT cells in vitro 36
4-11 MIF promotes the transmigration of CD56+CD3+ NKT cells in a CD74- and CXCR2-mediated manners 36
4-12 CD74+CXCR2+ mNKT cells are present in TPA-treated skin tissues 38
4-13 NK1.1 depletion attenuates TPA-induced ear swelling, CD54 expression, and granulocyte infiltration 38
4-14 MIF triggers the recruitment of mNKT cells in vivo 39
Chapter 5 Conclusion 40
Chapter 6 Discussion 41
6-1 The pathogenic roles of MIF and GSK-3 compared with this study and others in psoriasis 41
6-2 The effect of TPA and MIF challenges in isolated NKT, NK, and T cells in vitro for IFN-γ production 42
6-3 The unique findings of a subtype NKT cells 43
6-4 The potential effects of chemokine receptors for NKT cells 44
6-5 The effect of GSK-3 for IFN-γ production and IFN-γ signaling 45
6-6 The importance of GSK-3 activation in TPA-induced skin inflammation 46
6-7 The role of GSK-3 for human psoriatic therapy 47
6-8 The role of Gr-1+ cells in human psoriasis 48
Chapter 7 References 49
Table 1. The experimental animal models of psoriatic-like skin inflammation. 57
Figure 1. IFNGR1 deficiency attenuates TPA-induced acute skin inflammation, including ear swelling, granulocyte infiltration, and CD54 expression, but not CD3+ cell infiltration. 58
Figure 2. TPA induces GSK-3 activation followed by GSK-3-regulation of IFN-γ signaling. 59
Figure 3. Inhibiting GSK-3 decreases TPA-induced acute skin inflammation but not CD3+ cell infiltration. 62
Figure 4. The depletion of granulocytes attenuates TPA-induced ear swelling. 63
Figure 5. Local knockdown of GSK-3 attenuates TPA-induced edema and granulocyte infiltration. 64
Figure 6. Inhibiting GSK-3 decreases TPA-induced IFN-γ production and T-bet nuclear translocation. 65
Figure 7. Inhibiting GSK-3 attenuates chronic TPA-induced psoriasis-like skin inflammation including ear swelling, epidermal proliferation, and angiogenesis. 66
Figure 8. TPA directly induces the release of MIF from damaged keratinoyctes in vivo and in vitro by non-apoptotic cell death, not by IL-1β, IL-6, and TNF-α. 68
Figure 9. MIF antagnoinst, ISO-1, decreases TPA-induced acute skin inflammation in mice. 70
Figure 10. MIF antagonist, ISO-1, decreases TPA-induced chronic skin inflammation in mice. 71
Figure 11. Targeting MIF reduces the TPA-induced infiltration of IFN-γ+ mNKT cells by the pharmacological inhibition. 74
Figure 12. Only CD56+CD3+ hNKT cells of human PBMCs secrete IFN-γ after being sensitive to TPA, not CD4+, CD8+, or hNK. 75
Figure 13. MIF may trigger the transmigration activity of CD44+CD74+CXCR2+CXCR4+CD56brightCD3+ hNKT cells. 78
Figure 14. The recruitment of dermal CD74+CXCR2+NK1.1+CD3+ mNKT cells display a critical pathogenic role in TPA-induced skin inflammatory mice ears. 79
Figure 15. The murine NK1.1+ cells display a critical pathogenic role in TPA-induced skin inflammatory mice ears. 80
Figure 16. MIF antagonist, ISO-1, treatment reduced MIF-triggered recruitment of CD74+ or CXCR2+ mNKT cells. 81
Figure 17. MIF triggered the chemotaxis of CD74+CXCR2+NKT cells and GSK-3 facilitated IFN-γ production in NKT as well as IFNGR/STAT1 signaling in epidermal keratinocytes, determine the TPA-induced IFN-γ-mediated skin inflammation. 83
Appendix I. The morphology and characteristics of human psoriatic lesion. 84
Appendix II. A hypothetic immunopathogenesis of psoriasis. 85
Appendix III. GSK-3 facilitates IFN-γ signaling by sustaining STAT1 activation. 86
Appendix IV. IFN-γ promotes Th17-mediated immune responses in psoriatic lesions. 87
Appendix V. GSK-3 positively mediates T-bet nuclear translocation and Th1 development. 88
Appendix VI. The pathogenic role of MIF in skin dermatitis. 89
Appendix VII. MIF signaling via the functional receptors complex of CD74, CD44, CD182 (CXCR2), and CD184 (CXCR4). 90
Appendix VIII. MIF antagonist, ISO-1, blocks the interaction between MIF and its receptors. 91
Curriculum Vitae 92
Abdallah MA, Abdel-Hamid MF, Kotb AM and Mabrouk EA (2009) Serum interferon-gamma is a psoriasis severity and prognostic marker. Cutis 84:163-168.
Abe R, Shimizu T, Ohkawara A and Nishihira J (2000) Enhancement of macrophage migration inhibitory factor (MIF) expression in injured epidermis and cultured fibroblasts. Biochim Biophys Acta 1500:1-9.
Al-Abed Y and VanPatten S (2011) MIF as a disease target: ISO-1 as a proof-of-concept therapeutic. Future medicinal chemistry 3:45-63.
Ali A, Hoeflich KP and Woodgett JR (2001) Glycogen synthase kinase-3: properties, functions, and regulation. Chem Rev 101:2527-2540.
Balato A, Unutmaz D and Gaspari AA (2009) Natural killer T cells: an unconventional T-cell subset with diverse effector and regulatory functions. The Journal of investigative dermatology 129:1628-1642.
Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L, Kooistra T, Fingerle-Rowson G, Ghezzi P, Kleemann R, McColl SR, Bucala R, Hickey MJ and Weber C (2007) MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nature medicine 13:587-596.
Berzins SP, Smyth MJ and Baxter AG (2011) Presumed guilty: natural killer T cell defects and human disease. Nat Rev Immunol 11:131-142.
Beurel E, Michalek SM and Jope RS (2010) Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3). Trends Immunol 31:24-31.
Beurel E, Yeh WI, Michalek SM, Harrington LE and Jope RS (2011) Glycogen synthase kinase-3 is an early determinant in the differentiation of pathogenic Th17 cells. J Immunol 186:1391-1398.
Bonish B, Jullien D, Dutronc Y, Huang BB, Modlin R, Spada FM, Porcelli SA and Nickoloff BJ (2000) Overexpression of CD1d by keratinocytes in psoriasis and CD1d-dependent IFN-gamma production by NK-T cells. Journal of immunology 165:4076-4085.
Bos JD, de Rie MA, Teunissen MB and Piskin G (2005) Psoriasis: dysregulation of innate immunity. Br J Dermatol 152:1098-1107.
Bosschaerts T, Guilliams M, Stijlemans B, Morias Y, Engel D, Tacke F, Herin M, De Baetselier P and Beschin A (2010) Tip-DC development during parasitic infection is regulated by IL-10 and requires CCL2/CCR2, IFN-gamma and MyD88 signaling. PLoS Pathog 6:e1001045.
Cameron AL, Kirby B, Fei W and Griffiths CE (2002) Natural killer and natural killer-T cells in psoriasis. Archives of dermatological research 294:363-369.
Chuang YC, Lei HY, Liu HS, Lin YS, Fu TF and Yeh TM (2011) Macrophage migration inhibitory factor induced by dengue virus infection increases vascular permeability. Cytokine 54:222-231.
Cooper MA, Fehniger TA and Caligiuri MA (2001) The biology of human natural killer-cell subsets. Trends in immunology 22:633-640.
De Vry CG, Valdez M, Lazarov M, Muhr E, Buelow R, Fong T and Iyer S (2005) Topical application of a novel immunomodulatory peptide, RDP58, reduces skin inflammation in the phorbol ester-induced dermatitis model. The Journal of investigative dermatology 125:473-481.
Depianto D, Kerns ML, Dlugosz AA and Coulombe PA (2010) Keratin 17 promotes epithelial proliferation and tumor growth by polarizing the immune response in skin. Nat Genet 42:910-914.
Donn RP, Plant D, Jury F, Richards HL, Worthington J, Ray DW and Griffiths CE (2004) Macrophage migration inhibitory factor gene polymorphism is associated with psoriasis. The Journal of investigative dermatology 123:484-487.
Faure-Andre G, Vargas P, Yuseff MI, Heuze M, Diaz J, Lankar D, Steri V, Manry J, Hugues S, Vascotto F, Boulanger J, Raposo G, Bono MR, Rosemblatt M, Piel M and Lennon-Dumenil AM (2008) Regulation of dendritic cell migration by CD74, the MHC class II-associated invariant chain. Science 322:1705-1710.
Fry L and Baker BS (2007) Triggering psoriasis: the role of infections and medications. Clin Dermatol 25:606-615.
Fu M and Wang G (2012) Keratin 17 as a therapeutic target for the treatment of psoriasis. J Dermatol Sci 67:161-165.
Gesser B, Rasmussen MK, Raaby L, Rosada C, Johansen C, Kjellerup RB, Kragballe K and Iversen L (2011) Dimethylfumarate inhibits MIF-induced proliferation of keratinocytes by inhibiting MSK1 and RSK1 activation and by inducing nuclear p-c-Jun (S63) and p-p53 (S15) expression. Inflammation research : official journal of the European Histamine Research Society [et al] 60:643-653.
Gilhar A, Ullmann Y, Kerner H, Assy B, Shalaginov R, Serafimovich S and Kalish RS (2002) Psoriasis is mediated by a cutaneous defect triggered by activated immunocytes: induction of psoriasis by cells with natural killer receptors. The Journal of investigative dermatology 119:384-391.
Gilliver SC, Emmerson E, Bernhagen J and Hardman MJ (2011) MIF: a key player in cutaneous biology and wound healing. Experimental dermatology 20:1-6.
Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ and Van Kaer L (2004) NKT cells: what's in a name? Nat Rev Immunol 4:231-237.
Gorbachev AV and Fairchild RL (2006) Activated NKT cells increase dendritic cell migration and enhance CD8+ T cell responses in the skin. European journal of immunology 36:2494-2503.
Grandjean EM and Aubry JM (2009) Lithium: updated human knowledge using an evidence-based approach: part III: clinical safety. CNS Drugs 23:397-418.
Hald A, Andres RM, Salskov-Iversen ML, Kjellerup RB, Iversen L and Johansen C (2013) STAT1 expression and activation is increased in lesional psoriatic skin. The British journal of dermatology 168:302-310.
Hampton PJ, Jans R, Flockhart RJ, Parker G and Reynolds NJ (2011) Lithium regulates keratinocyte proliferation via glycogen synthase kinase 3 and NFAT2 (nuclear factor of activated T cells 2). J Cell Physiol.
Hedrick MN, Lonsdorf AS, Shirakawa AK, Richard Lee CC, Liao F, Singh SP, Zhang HH, Grinberg A, Love PE, Hwang ST and Farber JM (2009) CCR6 is required for IL-23-induced psoriasis-like inflammation in mice. J Clin Invest 119:2317-2329.
Hoi AY, Hickey MJ, Hall P, Yamana J, O'Sullivan KM, Santos LL, James WG, Kitching AR and Morand EF (2006) Macrophage migration inhibitory factor deficiency attenuates macrophage recruitment, glomerulonephritis, and lethality in MRL/lpr mice. J Immunol 177:5687-5696.
Hong K, Chu A, Ludviksson BR, Berg EL and Ehrhardt RO (1999) IL-12, independently of IFN-gamma, plays a crucial role in the pathogenesis of a murine psoriasis-like skin disorder. J Immunol 162:7480-7491.
Hsieh CY, Chen CL, Tsai CC, Huang WC, Tseng PC, Lin YS, Chen SH, Wong TW, Choi PC and Lin CF (2012) Inhibiting glycogen synthase kinase-3 decreases 12-O-tetradecanoylphorbol-13-acetate-induced interferon-gamma-mediated skin inflammation. The Journal of pharmacology and experimental therapeutics 343:125-133.
Hwang ES, Hong JH and Glimcher LH (2005) IL-2 production in developing Th1 cells is regulated by heterodimerization of RelA and T-bet and requires T-bet serine residue 508. The Journal of experimental medicine 202:1289-1300.
Ikeda S, Takahashi H, Suga Y, Eto H, Etoh T, Okuma K, Takahashi K, Kanbara T, Seishima M, Morita A, Imai Y and Kanekura T (2013) Therapeutic depletion of myeloid lineage leukocytes in patients with generalized pustular psoriasis indicates a major role for neutrophils in the immunopathogenesis of psoriasis. Journal of the American Academy of Dermatology 68:609-617.
Ikuta S, Edamatsu H, Li M, Hu L and Kataoka T (2008) Crucial role of phospholipase C epsilon in skin inflammation induced by tumor-promoting phorbol ester. Cancer Res 68:64-72.
Inacio AR, Ruscher K, Leng L, Bucala R and Deierborg T (2011) Macrophage migration inhibitory factor promotes cell death and aggravates neurologic deficits after experimental stroke. J Cereb Blood Flow Metab 31:1093-1106.
Jablonska J, Leschner S, Westphal K, Lienenklaus S and Weiss S (2010) Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model. J Clin Invest 120:1151-1164.
Jacobs R, Hintzen G, Kemper A, Beul K, Kempf S, Behrens G, Sykora KW and Schmidt RE (2001) CD56bright cells differ in their KIR repertoire and cytotoxic features from CD56dim NK cells. European journal of immunology 31:3121-3127.
Johnson-Huang LM, Suarez-Farinas M, Pierson KC, Fuentes-Duculan J, Cueto I, Lentini T, Sullivan-Whalen M, Gilleaudeau P, Krueger JG, Haider AS and Lowes MA (2012) A single intradermal injection of IFN-gamma induces an inflammatory state in both non-lesional psoriatic and healthy skin. J Invest Dermatol 132:1177-1187.
Johnston B, Kim CH, Soler D, Emoto M and Butcher EC (2003) Differential chemokine responses and homing patterns of murine TCR alpha beta NKT cell subsets. Journal of immunology 171:2960-2969.
Kai JI, Huang WC, Tsai CC, Chang WT, Chen CL and Lin CF (2010) Glycogen synthase kinase-3beta indirectly facilitates interferon-gamma-induced nuclear factor-kappaB activation and nitric oxide biosynthesis. J Cell Biochem 111:1522-1530.
Klein-Szanto AJ, Chiba M, Lee SU, Conti CJ and Thetford D (1984) Keratinocyte damage produced by 12-O-tetradecanoylphorbol-13-acetate in rodent epidermis. Carcinogenesis 5:1459-1465.
Knijff EM, Kupka RW, Ruwhof C, Breunis MN, Prens EP, Nolen WA and Drexhage HA (2005) Evidence that the immunopathogenic mechanism of lithium-induced psoriasis differs from that of regular psoriasis. Bipolar Disord 7:388-389.
Kryczek I, Bruce AT, Gudjonsson JE, Johnston A, Aphale A, Vatan L, Szeliga W, Wang Y, Liu Y, Welling TH, Elder JT and Zou W (2008) Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis. J Immunol 181:4733-4741.
Kupper TS and Fuhlbrigge RC (2004) Immune surveillance in the skin: mechanisms and clinical consequences. Nature reviews Immunology 4:211-222.
Lai Y, Di Nardo A, Nakatsuji T, Leichtle A, Yang Y, Cogen AL, Wu ZR, Hooper LV, Schmidt RR, von Aulock S, Radek KA, Huang CM, Ryan AF and Gallo RL (2009) Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury. Nat Med 15:1377-1382.
Leng L, Chen L, Fan J, Greven D, Arjona A, Du X, Austin D, Kashgarian M, Yin Z, Huang XR, Lan HY, Lolis E, Nikolic-Paterson D and Bucala R (2011) A small-molecule macrophage migration inhibitory factor antagonist protects against glomerulonephritis in lupus-prone NZB/NZW F1 and MRL/lpr mice. Journal of immunology 186:527-538.
Lin CF, Tsai CC, Huang WC, Wang CY, Tseng HC, Wang Y, Kai JI, Wang SW and Cheng YL (2008) IFN-gamma synergizes with LPS to induce nitric oxide biosynthesis through glycogen synthase kinase-3-inhibited IL-10. J Cell Biochem 105:746-755.
Lowes MA, Bowcock AM and Krueger JG (2007) Pathogenesis and therapy of psoriasis. Nature 445:866-873.
Ma HL, Liang S, Li J, Napierata L, Brown T, Benoit S, Senices M, Gill D, Dunussi-Joannopoulos K, Collins M, Nickerson-Nutter C, Fouser LA and Young DA (2008) IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation. J Clin Invest 118:597-607.
Maier M, Wutzler S, Bauer M, Trendafilov P, Henrich D and Marzi I (2008) Altered gene expression patterns in dendritic cells after severe trauma: implications for systemic inflammation and organ injury. Shock 30:344-351.
Marchetti S, Gamas P, Belhacene N, Grosso S, Pradelli LA, Colosetti P, Johansen C, Iversen L, Deckert M, Luciano F, Hofman P, Ortonne N, Khemis A, Mari B, Ortonne JP, Ricci JE and Auberger P (2009) The caspase-cleaved form of LYN mediates a psoriasis-like inflammatory syndrome in mice. EMBO J 28:2449-2460.
Medina M and Avila J (2010) Glycogen synthase kinase-3 (GSK-3) inhibitors for the treatment of Alzheimer's disease. Curr Pharm Des 16:2790-2798.
Nakajima A, Matsuki T, Komine M, Asahina A, Horai R, Nakae S, Ishigame H, Kakuta S, Saijo S and Iwakura Y (2010) TNF, but not IL-6 and IL-17, is crucial for the development of T cell-independent psoriasis-like dermatitis in Il1rn-/- mice. J Immunol 185:1887-1893.
Nestle FO, Kaplan DH and Barker J (2009) Psoriasis. The New England journal of medicine 361:496-509.
Nickoloff BJ, Wrone-Smith T, Bonish B and Porcelli SA (1999) Response of murine and normal human skin to injection of allogeneic blood-derived psoriatic immunocytes: detection of T cells expressing receptors typically present on natural killer cells, including CD94, CD158, and CD161. Arch Dermatol 135:546-552.
Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, Hall CF, Darst MA, Gao B, Boguniewicz M, Travers JB and Leung DY (2003) Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. Journal of immunology 171:3262-3269.
Novak J, Griseri T, Beaudoin L and Lehuen A (2007) Regulation of type 1 diabetes by NKT cells. Int Rev Immunol 26:49-72.
Oberg F, Wu S, Bahram F, Nilsson K and Larsson LG (2001) Cytokine-induced restoration of differentiation and cell cycle arrest in v-Myc transformed U-937 monoblasts correlates with reduced Myc activity. Leukemia 15:217-227.
Park SY, Gupta D, Hurwich R, Kim CH and Dziarski R (2011) Peptidoglycan recognition protein Pglyrp2 protects mice from psoriasis-like skin inflammation by promoting regulatory T cells and limiting Th17 responses. Journal of immunology 187:5813-5823.
Pazyar N, Feily A and Yaghoobi R (2013) Macrophage migration inhibitory factor as an incriminating agent in dermatological disorders. Indian journal of dermatology 58:157.
Peternel S and Kastelan M (2009) Immunopathogenesis of psoriasis: focus on natural killer T cells. Journal of the European Academy of Dermatology and Venereology : JEADV 23:1123-1127.
Poli A, Michel T, Theresine M, Andres E, Hentges F and Zimmer J (2009) CD56bright natural killer (NK) cells: an important NK cell subset. Immunology 126:458-465.
Roger T, David J, Glauser MP and Calandra T (2001) MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature 414:920-924.
Schoenborn JR and Wilson CB (2007) Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 96:41-101.
Schon MP (2008) Animal models of psoriasis: a critical appraisal. Experimental dermatology 17:703-712.
Schon MP and Boehncke WH (2005) Psoriasis. The New England journal of medicine 352:1899-1912.
Shimizu T (2005) Role of macrophage migration inhibitory factor (MIF) in the skin. Journal of dermatological science 37:65-73.
Shimizu T, Nishihira J, Mizue Y, Nakamura H, Abe R, Watanabe H, Ohkawara A and Shimizu H (2001) High macrophage migration inhibitory factor (MIF) serum levels associated with extended psoriasis. The Journal of investigative dermatology 116:989-990.
Simoni Y, Diana J, Ghazarian L, Beaudoin L and Lehuen A (2013) Therapeutic manipulation of natural killer (NK) T cells in autoimmunity: are we close to reality? Clin Exp Immunol 171:8-19.
Singh TP, Lee CH and Farber JM (2013) Chemokine receptors in psoriasis. Expert opinion on therapeutic targets 17:1405-1422.
Steinhoff M, Meinhardt A, Steinhoff A, Gemsa D, Bucala R and Bacher M (1999) Evidence for a role of macrophage migration inhibitory factor in psoriatic skin disease. The British journal of dermatology 141:1061-1066.
Strid J, Tigelaar RE and Hayday AC (2009) Skin immune surveillance by T cells--a new order? Semin Immunol 21:110-120.
Swamy M, Jamora C, Havran W and Hayday A (2010) Epithelial decision makers: in search of the 'epimmunome'. Nature immunology 11:656-665.
Swindell WR, Johnston A, Xing X, Voorhees JJ, Elder JT and Gudjonsson JE (2013) Modulation of epidermal transcription circuits in psoriasis: new links between inflammation and hyperproliferation. PLoS One 8:e79253.
Szegedi A, Aleksza M, Gonda A, Irinyi B, Sipka S, Hunyadi J and Antal-Szalmas P (2003) Elevated rate of Thelper1 (T(H)1) lymphocytes and serum IFN-gamma levels in psoriatic patients. Immunology letters 86:277-280.
Takahashi H, Tsuji H, Hashimoto Y, Ishida-Yamamoto A and Iizuka H (2010) Serum cytokines and growth factor levels in Japanese patients with psoriasis. Clin Exp Dermatol 35:645-649.
Tarutani M, Imai Y, Yasuda K, Tsutsui H, Nakanishi K and Yamanishi K (2010) Neutrophil-dominant psoriasis-like skin inflammation induced by epidermal-specific expression of Raf in mice. Journal of dermatological science 58:28-35.
Terrazas CA, Juarez I, Terrazas LI, Saavedra R, Calleja EA and Rodriguez-Sosa M (2010) Toxoplasma gondii: impaired maturation and pro-inflammatory response of dendritic cells in MIF-deficient mice favors susceptibility to infection. Exp Parasitol 126:348-358.
Tobin AM, Lynch L, Kirby B and O'Farrelly C (2011) Natural killer cells in psoriasis. Journal of innate immunity 3:403-410.
Tsai CC, Huang WC, Chen CL, Hsieh CY, Lin YS, Chen SH, Yang KC and Lin CF (2011) Glycogen synthase kinase-3 facilitates con a-induced IFN-gamma-- mediated immune hepatic injury. J Immunol 187:3867-3877.
Tsai CC, Kai JI, Huang WC, Wang CY, Wang Y, Chen CL, Fang YT, Lin YS, Anderson R, Chen SH, Tsao CW and Lin CF (2009) Glycogen synthase kinase-3beta facilitates IFN-gamma-induced STAT1 activation by regulating Src homology-2 domain-containing phosphatase 2. Journal of immunology 183:856-864.
van der Fits L, Mourits S, Voerman JS, Kant M, Boon L, Laman JD, Cornelissen F, Mus AM, Florencia E, Prens EP and Lubberts E (2009) Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol 182:5836-5845.
von Bubnoff D, Andres E, Hentges F, Bieber T, Michel T and Zimmer J (2010) Natural killer cells in atopic and autoimmune diseases of the skin. The Journal of allergy and clinical immunology 125:60-68.
Wagner EF, Schonthaler HB, Guinea-Viniegra J and Tschachler E (2010) Psoriasis: what we have learned from mouse models. Nat Rev Rheumatol 6:704-714.
Wang H, Brown J and Martin M (2011) Glycogen synthase kinase 3: a point of convergence for the host inflammatory response. Cytokine 53:130-140.
Weiss JM, Sleeman J, Renkl AC, Dittmar H, Termeer CC, Taxis S, Howells N, Hofmann M, Kohler G, Schopf E, Ponta H, Herrlich P and Simon JC (1997) An essential role for CD44 variant isoforms in epidermal Langerhans cell and blood dendritic cell function. J Cell Biol 137:1137-1147.
Wolk K, Haugen HS, Xu W, Witte E, Waggie K, Anderson M, Vom Baur E, Witte K, Warszawska K, Philipp S, Johnson-Leger C, Volk HD, Sterry W and Sabat R (2009a) IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-gamma are not. J Mol Med 87:523-536.
Wolk K, Witte E, Warszawska K, Schulze-Tanzil G, Witte K, Philipp S, Kunz S, Docke WD, Asadullah K, Volk HD, Sterry W and Sabat R (2009b) The Th17 cytokine IL-22 induces IL-20 production in keratinocytes: a novel immunological cascade with potential relevance in psoriasis. Eur J Immunol 39:3570-3581.
Wong BL, Zhu SL, Huang XR, Ma J, Xia HH, Bucala R, Wong BC and Lan HY (2009) Essential role for macrophage migration inhibitory factor in gastritis induced by Helicobacter pylori. The American journal of pathology 174:1319-1328.
Wu J, Chen F, Zhang X, Li Y, Ma H, Zhou Y, Jin Y, Wang H, Bai J, Zhang G and Fu S (2009) Association of MIF promoter polymorphisms with psoriasis in a Han population in northeastern China. Journal of dermatological science 53:212-215.
Xiao M, Wang C, Zhang J, Li Z, Zhao X and Qin Z (2009) IFNgamma promotes papilloma development by up-regulating Th17-associated inflammation. Cancer Res 69:2010-2017.
Yao Y, Richman L, Morehouse C, de los Reyes M, Higgs BW, Boutrin A, White B, Coyle A, Krueger J, Kiener PA and Jallal B (2008) Type I interferon: potential therapeutic target for psoriasis? PloS one 3:e2737.
Zernecke A, Bernhagen J and Weber C (2008) Macrophage migration inhibitory factor in cardiovascular disease. Circulation 117:1594-1602.
Zhao Y, Fishelevich R, Petrali JP, Zheng L, Anatolievna MA, Deng A, Eckert RL and Gaspari AA (2008) Activation of keratinocyte protein kinase C zeta in psoriasis plaques. J Invest Dermatol 128:2190-2197.