Background/Purpose: Systemic lupus erythematosus (SLE) is a devastating autoimmune disease with severe complications such as immune-complex mediated nephritis and scarring skin lesions.  Treatment modalities for cutaneous lesions are often ineffective and pathogenic mechanisms driving rash development remain poorly understood.  Interleukin-6 (IL-6) is a pro-inflammatory cytokine which has gotten recent attention in SLE as IL-6 is increased in the serum of active patients and blockade of IL-6 is therapeutic in several murine lupus models.  Further, several phase I human trials have suggested IL-6 blockade may be promising for treatment of SLE.  However, the role that IL-6 plays in cutaneous lupus erythematosus (CLE) rashes remains unclear.

Methods: All studies were approved by the University of Michigan Internal Review Board (IRB# 72843 and 66116). RNA was isolated from formalin fixed, paraffin-embedded biopsies of CLE rashes, which were obtained from the University of Michigan Pathology database.  Real-time PCR was used to determine the expression level of the myxovirus (influenza virus) resistance 1 (MX-1) and interleukin-6 (IL6) genes. Biopsies were stained for IL-6 using immunohistochemistry.    Skin biopsies were obtained from uninvolved skin of SLE patients with a history of cutaneous involvement or healthy controls followed by isolation and culture of keratinocytes.  At confluence, cultures were treated with various concentrations of TLR ligands or UVB and IL-6 release was measured via ELISA.

Results: Real-time PCR analysis of subacute cutaneous lupus erythematosus (sCLE) (n=21) and discoid (DLE) (n=22) rashes demonstrated a significant upregulation of both the IFN-regulated gene, MX1, and the pro-inflammatory cytokine IL-6 when compared with control samples (n=9). Immunohistochemical analysis of skin biopsies confirmed upregulation of IL-6 in the epidermis when compared to control. Keratinocytes from healthy skin of lupus patients produced significantly more IL-6 when stimulated by TLR2, 3 or 4 agonists or exposed to UVB radiation when compared to identical passage keratinocytes from healthy controls.

Conclusion: IL-6 is increased at the RNA and protein level within cutaneous lupus biopsies when compared to healthy control skin.  Keratinocytes are a major producer of IL-6 in the skin and lupus keratinocytes have enhanced production of IL-6 in response to TLR ligands and UV radiation. These data suggest that the epidermis, which is an important barrier for environmental insults, is primed for IL-6 production and that this may be one mechanism by which factors such as UV exposure may trigger rash development. Further investigations should focus on the pathogenic significance of IL-6 upregulation in the skin and whether targeting this pathway will have an impact on cutaneous disease activity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/keratinocyte-associated-il-6-is-elevated-in-cutaneous-lupus-rashes-and-production-of-il-6-by-keratinocytes-is-enhanced-in-non-involved-lupus-skin/