Impaired IFN-γ-Dependent Inflammatory Responses in Human Keratinocytes Overexpressing the Suppressor of Cytokine Signaling 1

Abstract

Keratinocytes contribute relevantly to the pathogenesis of inflammatory skin diseases by expressing a variety of proinflammatory molecules, with T cell-derived IFN-γ being the most potent keratinocyte activator. Suppressor of cytokine signaling (SOCS)1 and SOCS3 are negative regulators of IFN-γ signaling and are induced in many cell types by IFN-γ itself or by other cytokines. We show in this work that SOCS1, SOCS2, SOCS3, and cytokine-inducible SH2-containing protein mRNA were up-regulated by IFN-γ in normal human keratinocytes, whereas only SOCS1 or SOCS1 and cytokine-inducible SH2-containing protein were induced by TNF-α or IL-4, respectively. SOCS1, SOCS2, and SOCS3 proteins were undetectable in healthy skin and highly expressed in the epidermis of psoriasis and allergic contact dermatitis, but were only weakly expressed in atopic dermatitis skin. In keratinocytes transiently transfected with SOCS1 or SOCS3 the IFN-γ-induced transactivation of an IFN-γ-responsive reporter gene was markedly inhibited. SOCS1 and SOCS3 overexpression in keratinocyte stable clones inhibited IFN-γ-induced phosphorylation of IFN-γRα and activation of STAT1 and STAT3. Furthermore, SOCS1 and, to a lesser extent, SOCS3 reduced membrane expression of ICAM-1 and HLA-DR, and release of IFN-γ-inducible protein-10, monokine induced by IFN-γ, and monocyte chemoattractant protein-1 by keratinocyte clones promoted by IFN-γ. SOCS1-expressing keratinocytes showed constitutively higher, but not IFN-γ-inducible, IL-8 levels compared with SOCS2 and SOCS3 clones, and were resistant to IFN-γ-mediated growth inhibition. Targeting keratinocyte SOCS1 may represent a novel therapeutic approach to IFN-γ-dependent skin diseases.

Acute and persisting Th2-like immune response after fractionated colorectal γ-irradiation

“…A particularly interesting candidate from this family is SOCS3, known to interfere with the IFNγ/Stat-1 pathway [19,20] . Western blot analysis showed the SOCS3 protein levels remained high at 26 wk after irradiation (P < 0.05) ( Figure 6A).…”

A Second Step of Chemotaxis After Transendothelial Migration: Keratinocytes Undergoing Apoptosis Release IFN-γ-Inducible Protein 10, Monokine Induced by IFN-γ, and IFN-γ-Inducible α-Chemoattractant for T Cell Chemotaxis Toward Epidermis in Atopic Dermatitis

“…Apoptosis of keratinocytes induced by T cells and mediated by IFN-␥ and Fas (CD95) is a crucial event in the transition from activation of the immune system to the manifestation of eczematous dermatitis (23). Apparently, keratinocyte apoptosis is an activation-induced cell death, because IFN-␥ up-regulates Fas, ICAM-1, and HLA-DR and renders keratinocytes susceptible to apoptosis (24). Induction of keratinocyte apoptosis by skin-infiltrating T cells, subsequent cleavage of E-cadherin, and resisting desmosomal cadherins represent molecular events in spongiosis formation (25).…”

Thrombin induces expression of cytokine‐induced SH2 protein (CIS) in rat brain astrocytes: Involvement of phospholipase A2, cyclooxygenase, and lipoxygenase

“…quently, SOCS1 and SOCS3 inhibit activation of STAT1 and STAT3. By this mechanism, SOCS1 and SOCS3 reduce IFN-␥-induced expression of intercellular adhesion molecule-1 (ICAM-1), HLA-DR, IFN-␥-inducible protein-10 (IP-10) and monocyte chemoattractant protein-1 (MCP-1) (Federici et al, 2002). In SOCS3 mutant transgenic mice, stronger STAT3 activation and more severe colitis were detected compared to those in wild type mice (Suzuki et al, 2001).…”