Keratinocyte CDw60 expression is modulated by both a Th-1 type cytokine IFN-gamma and Th-2 cytokines IL-4 and IL-13: relevance to psoriasis.
Psoriasis is a chronic skin disease with an immunocytic infiltrate, including activated T lymphocytes, producing multiple cytokines that can influence the phenotype of epidermal keratinocytes. In these studies we examined the effect of the cytokines interferon-gamma and interleukin-13 or interleukin-4 on keratinocytes, alone and in combination, on surface levels of HLA-DR, intercellular adhesion molecule 1, and CDw60, as well as the transcription factors STAT1, STAT6, and BCL-6. As CDw60 is an acetylated form of the GD3 ganglioside and may function as a T cell costimulatory molecule, the modulation of CDw60 expression by keratinocytes in psoriatic lesions was highlighted to gain insight into potentially important T cell-keratinocyte interactions. Interferon-gamma was observed to block the interleukin-4- or interleukin-13-mediated induction of CDw60 on cultured keratinocytes, but not induction of the transcription factor STAT6. Interleukin-13 and interleukin-4 were unable to block interferon-gamma-mediated induction of STAT1 or BCL-6, however, or the upregulation of intercellular adhesion molecule 1 and HLA-DR. In psoriatic plaques, CDw60 was not consistently detected on keratinocytes in acute lesions, but was detected predominantly on basal layer keratinocytes in chronic lesions. In addition we found that BCL-6 levels were increased in psoriatic lesions; in acute lesions BCL-6 was primarily localized in the basal layer keratinocytes, whereas in chronic plaques nuclear BCL-6 was predominantly expressed by keratinocytes in the suprabasal cell layers. These studies highlight the complex modulation of the keratinocyte phenotype by immunocyte-derived cytokines, in which induction of CDw60 involving interleukin-4, or interleukin-13 was antagonized by interferon-gamma. We suggest in psoriatic plaques that the presence or absence of CDw60 expression by keratinocytes may reflect the dynamic interplay between Th-1-type cytokines such as interferon-gamma and Th-2-type cytokines such as interleukin-4 and interleukin-13. The ability of interferon-gamma to induce the transcription repressor BCL-6 may also contribute to the overall immunologic events in skin, including suppression of the intermediates in the synthetic pathway leading to expression of the T cell costimulatory ganglioside CDw60.
Huang
B B
BB
Department of Pathology, Loyola University Medical Center, Maywood, IL 60153, USA.
Bonish
B K
BK
Chaturvedi
V
V
Qin
J Z
JZ
Nickoloff
B J
BJ
D000208:Acute Disease; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis*; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000494:pharmacology*; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D015603:Keratinocytes / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D051560:Proto-Oncogene Proteins c-bcl-6; D011565:Psoriasis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; D012867:Skin / Q000737:chemistry / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis / Q000187:drug effects; D014157:Transcription Factors / Q000096:biosynthesis
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; C064741:CDw60 antigen; D004268:DNA-Binding Proteins; D018793:Interleukin-13; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494080:Stat1 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D015847:Interleukin-4; D007371:Interferon-gamma