Abstract
Recently, we have reported a rapid and strong induction of interleukin-18 (IL-18) upon cutaneous injury in mice. In this paper, we investigated a possible role of IL-18 in triggering interferon-gamma (IFN-gamma) production at the wound site. Expression of IFN-gamma during cutaneous wound healing was analyzed by RNase protection assay, Western blot, ELISA, and immunohistochemical techniques in a murine model of excisional skin repair. We could not detect any IFN-gamma mRNA and protein expression during normal skin repair. Additionally, impaired healing in the genetically diabetic db/db mouse, which was used as a model for a prolonged inflammatory phase of repair, was characterized by largely elevated levels of IL-18 during the late phase of repair and an absence of IFN-gamma. Western blot analysis for T-cell- and monocyte/macrophage-specific marker proteins (CD4, F4/80) clearly revealed the presence of these subsets of leukocytic cells at the wound site, that are known to produce IFN-gamma in response to IL-18. Furthermore, we provide evidence that the presence of transforming growth factor-beta1 (TGF-beta1) at the wound site might reflect a counterregulatory mechanism in IL-18-induced IFN-gamma production, as TGF-beta1 strongly suppressed IL-18/phytohaemagglutinin (PHA)-induced IFN-gamma production by peripheral blood mononuclear cells (PBMC) in vitro. Normal tissue regeneration processes after cutaneous injury were not dependent on the presence of IFN-gamma in vivo, and IL-18 must serve additional roles rather than inducing IFN-gamma during the healing process.
Highlights
Interferon (IFN)-␣, -, and -␥ represent modulators of fibrous responses for a variety of mesenchymal cells in vitro
As the production of IFN-␥ might be associated with the inflammatory phase of repair, we have determined IL-18 expression and immigration of the T helper (Th)/macrophage subset of leukocytes during healing in the genetically diabetic db/db mouse, which is characterized by a prolonged inflammatory phase of repair [30]
As IL-18-stimulated monocytic cells have been described to produce IFN-␥ [13], we determined the presence of F4/80 antigen at the wound site, which represents a 160-kDa glycoprotein that is expressed by murine macrophages [32]
Summary
Interferon (IFN)-␣, -, and -␥ represent modulators of fibrous responses for a variety of mesenchymal cells in vitro. Using a murine wound-healing model, systemic administration of IFN-␥ upon injury decreased wound collagen deposition and clearly reduced the initial inflammatory response [12] indicating a role for this mediator in the control of excessive matrix synthesis during repair. As IFN-␥ clearly reduced wound collagen synthesis [12], the absence of IFN-␥-producing lymphocytes should lead to opposite effects. As expression of the IFN-␥-inducing cytokine IL-18 temporally precedes the infiltration of T-lymphocytes upon injury [20], we raised the question of a general presence of IFN-␥ during cutaneous healing. Conclusions: Normal tissue regeneration processes after cutaneous injury were not dependent on the presence of IFN-␥ in vivo, and IL-18 must serve additional roles rather than inducing IFN-␥ during the healing process
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