Protein Expression of TNF-α in Psoriatic Skin Is Regulated at a Posttranscriptional Level by MAPK-Activated Protein Kinase 2

Abstract

Alterations in specific signal transduction pathways may explain the increased expression of proinflammatory cytokines seen in inflammatory diseases such as psoriasis. We reveal increased TNF-α protein expression, but similar TNF-α mRNA levels, in lesional compared with nonlesional psoriatic skin, demonstrating for the first time that TNF-α expression in lesional psoriatic skin is regulated posttranscriptionally. Increased levels of activated MAPK-activated protein kinase 2 (MK2) together with increased MK2 kinase activity were found in lesional compared with nonlesional psoriatic skin. Immunohistochemical analysis showed that activated MK2 was located in the basal layers of the psoriatic epidermis, whereas no positive staining was seen in nonlesional psoriatic skin. In vitro experiments demonstrated that both anisomycin and IL-1β caused a significant activation of p38 MAPK and MK2 in cultured normal human keratinocytes. In addition, TNF-α protein levels were significantly up-regulated in keratinocytes stimulated with anisomycin or IL-1β. This increase in TNF-α protein expression was completely blocked by the p38 inhibitor, SB202190. Transfection of cultured keratinocytes with MK2-specific small interfering RNA led to a significant decrease in MK2 expression and a subsequent significant reduction in the protein expression of the proinflammatory cytokines TNF-α, IL-6, and IL-8, whereas no change in the expression of the anti-inflammatory cytokine IL-10 was seen. This is the first time that MK2 expression and activity have been investigated in an inflammatory disease such as psoriasis. The results strongly suggest that increased activation of MK2 is responsible for the elevated and posttranscriptionally regulated TNF-α protein expression in psoriatic skin, making MK2 a potential target in the treatment of psoriasis.

IκBζ is a key driver in the development of psoriasis

“…Although several inflammatory factors, including TNFα and IL-17A, are known to play a major role in the pathogenesis of psoriasis (26,27), our understanding of the underlying molecular mechanisms remains limited. Intracellular signaling pathways and their role in psoriasis have recently attracted much interest, and signaling pathways such as the NF-κB, JAK/STAT, and p38 MAPK pathway have been demonstrated to be altered in psoriatic skin (11,(28)(29)(30).…”

Pentoxifylline attenuates nociceptive sensitization and cytokine expression in a tibia fracture rat model of complex regional pain syndrome

“…We postulate that the overexpressed cytokines observed in the hindpaw skin after fracture were produced by resident cells such as keratinocytes. These cells can produce TNFα, IL-6 and other cytokines in the settings of acute and chronic disease-related inflammation, traumatic injury, and after exposure to irritants (Allen et al 2000;Johansen et al 2006;Eming et al 2007). …”

An Anti-IL-12p40 Antibody Down-Regulates Type 1 Cytokines, Chemokines, and IL-12/IL-23 in Psoriasis

“…It is possible that TNF-␣ protein levels have a close relationship to the degree of inflammation (e.g., PASI score), and mRNA levels are indicative of a likely responder to the therapy. Posttranscriptional regulation and posttranslational processing are important in TNF-␣ protein production (73,74) and mRNA levels may also reflect increased half-life of mRNA. Because our study has only a limited number of patients, and TNF-␣ mRNA and protein processing is quite complicated, a more highly powered study specifically designed to address TNF-␣ levels and clinical improvement will be necessary to validate these observations.…”