IL-1 signalling determines the fate of skin grafts expressing non-self protein in keratinocytes

Exp Dermatol. 2010 Aug;19(8):723-9. doi: 10.1111/j.1600-0625.2010.01092.x.

Abstract

Although IL-1 is a known inflammatory cytokine during pathogen infection, the role of IL-1 in skin graft rejection, particularly where foreign antigen is expressed exclusively in keratinocytes, is less understood. Here, we use a syngeneic skin graft system, where antigens are expressed in epithelial cells via either a keratin 14 or keratin 5 promoter, to explore the role of IL-1 in graft rejection and induction of epithelial antigen-specific effector CD8(+) T-cell function. Keratin 5 ovalbumin (K5mOVA) transgenic skin grafts destined for rejection demonstrated increased expression of IL-1beta and its receptors compared to K14 HPV16 E7 transgenic grafts that do not reject spontaneously. Rejection of OVA grafts lacking the IL-1 receptor (IL-1R1) was delayed and associated with decreased numbers of antigen-specific CD8 T cells. In contrast, K14E7 grafts survived on immunocompetent, syngeneic recipients with decreased graft levels of IL-1beta and IL-1R1 and 2. However, in the absence of the IL-1 receptor antagonist, IL-1Ra, skin grafts were spontaneously rejected and an E7-specific CD8 T-cell response was primed. Thus, expression of the HPV16E7 oncoprotein in epithelial cells prevents IL-1beta-associated skin graft rejection and induction of antigen-specific CD8 T-cell responses. Enhancing IL-1beta signalling, via blocking of the IL-1 receptor antagonist, may represent an alternative strategy for treatment of HPV16E7-associated cancers.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Graft Rejection / metabolism
  • Interleukin-1 / metabolism*
  • Keratin-14 / metabolism
  • Keratin-5 / metabolism
  • Keratinocytes / cytology
  • Keratinocytes / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Animal
  • Ovalbumin / metabolism
  • Papillomavirus E7 Proteins / metabolism
  • Receptors, Interleukin-1 / metabolism
  • Signal Transduction / physiology*
  • Skin Transplantation / physiology*

Substances

  • Interleukin-1
  • Keratin-14
  • Keratin-5
  • Papillomavirus E7 Proteins
  • Receptors, Interleukin-1
  • oncogene protein E7, Human papillomavirus type 16
  • Ovalbumin