Transforming growth factor-/Smad3 signalling regulates inflammatory responses in a murine model of contact hypersensitivity

Abstract

BackgroundTransforming growth factor (TGF)-β is an important modulator of immune functions and cellular responses, such as differentiation, proliferation, migration and apoptosis. The Smad proteins, which are intracellular TGF-β signal transducers, mediate most actions of TGF-β.ObjectivesThis study examines the role of Smad3 in a murine model of contact hypersensitivity (CHS).MethodsThe CHS response to oxazolone was studied in Smad3-deficient mice. The ear swelling response was measured and skin biopsies from oxazolone-sensitized skin areas were obtained for RNA isolation, immunohistochemical analyses and histology. Ear draining lymph nodes were collected for RNA isolation and proliferation tests. Quantitative real-time polymerase chain reaction was used to quantify mRNA expression of cytokines, chemokines and transcription factors.ResultsThe expression of proinflammatory [interleukin (IL)-1β, tumour necrosis factor-α, IL-6], Th2 (IL-4) and Th17 type cytokines (IL-17), as well as regulatory components (TGF-β, Foxp3) increased significantly at the mRNA level in the skin of oxazolone-treated Smad3−/− mice when compared with wild-type controls. The expression of the Th1 type cytokine IFN-γ and the chemokines CXCL9 and CXCL10 was, however, unaffected by the lack of Smad3. The number of neutrophils and expression of the chemokines CCL3 and CXCL5, which are both involved in neutrophil recruitment, were increased in mice lacking Smad3. Also Th2 type chemokines CCL24, CCL3 and CXCL5 were increased in the skin of Smad3−/− mice compared with wild-type mice. In the lymph nodes, mRNA of IL-1β and IL-17, but not IL-4, TGF-β or Foxp3, was increased in Smad3−/− mice during the CHS response.ConclusionsThe lack of intact TGF-β signalling via Smad3 results in an increased proinflammatory, Th2 and Th17 type response in the skin, as well as increased expression of regulatory elements such as TGF-β and Foxp3. Understanding the role of Smad3 in the CHS response may offer treatment and prevention strategies in this often disabling disease.

TGF-β Is Required To Maintain the Pool of Immature Langerhans Cells in the Epidermis

“…This supports independent results that dermal DCs can drive CHS responses in the absence of LCs (30) and that TGF-b control of (dermal) DC function is dispensable to regulate the magnitude and duration of the reaction, although a role for TGF-b/SMAD3 signals to control inflammation during CHS has been suggested (46). Moreover, attenuated ear swelling in LC-deficient DC-TbR1 del mice argues against a regulatory role of LCs in CHS (47).…”

Histopathological features and expression profiles of cytokines, chemokines and SOCS family proteins in trehalose 6,6′-dimycolate-induced granulomatous lesions

“…One possible candidate is TGF-b, because this cytokine maintained a high expression level at 14 dpi, and there are reports regarding the induction of MCP-1 [35] and IP-10 [36] by the expression of TGF-b. In addition, the knocking out of SMAD3, a transducer of the TGF-b signaling, resulted in a higher expression of MIP-1a suggesting that TGFb suppresses the expression of MIP-1a [37].…”

Role of Smad and non-Smad Signals in the Development of Th17 and Regulatory T Cells

“…For example, SMAD3 is essential for the suppressive effect of TGF-β on IL-2 production and T cell proliferation (18). In addition, SMAD3 is also required for the suppressive effects of TGF-β on Th2-type cytokine productions and Th2-type disease in the skin (19). Tone et al (22) We have systematically investigated the role of SMAD2 or SMAD3 in the TGF-β-induced Foxp3 + iTreg cell induction both in vitro and in vivo.…”