Inhibition of IL-12 Production by Thalidomide
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. The Journal of Immunology
(Impact Factor: 4.92).
The immunomodulatory properties of thalidomide are currently being exploited therapeutically in conditions as diverse as erythema nodosum leprosum, chronic graft-vs-host disease, rheumatoid arthritis, and sarcoidosis. The relevant mechanism of action of thalidomide in these diseases remains unclear. The important role recently ascribed to IL-12, a cytokine critical to the development of cellular immune responses, in the pathogenesis of several of these conditions led us to examine whether thalidomide affects the production of IL-12. Thalidomide potently suppressed the production of IL-12 from human PBMC and primary human monocytes in a concentration-dependent manner. Thalidomide-induced inhibition of IL-12 production was additive to that induced by suboptimal inhibiting doses of dexamethasone, and occurred by a mechanism independent of known endogenous inhibitors of IL-12 production. These results suggest that thalidomide may have therapeutic utility in a wide range of immunologic disorders that are characterized by inappropriate cellular immune responses.
Available from: Claudio Guedes Salgado
- "Here, we also detected downregulation of TNF-α production by LPS-stimulated MΦ after thalidomide treatment. Furthermore, we found also that IL-12 production by unstimulated cultured LC was strongly suppressed by both concentrations of thalidomide, and that IL-12 secretion by LPS-stimulated MΦ was reduced by high concentrations of thalidomide (10-6 M), supporting previous studies showing that thalidomide inhibits IL-12 production by LPS-stimulated monocytes . Another study suggested suppression of TNF-α and IL-12 as a possible mechanism of thalidomide's clinical effects in Crohn's disease, which improves clinical symptoms in patients , what may explain its clinical efficacy. "
[Show abstract] [Hide abstract]
ABSTRACT: Langerhans cells constitute a special subset of immature dendritic cells localized in the epidermis that play a key role in the skin's immune response. The production of cytokines is a key event in both the initiation and the regulation of immune responses, and different drugs can be used to remove or modify their production by DC and, therefore, alter immune responses in a broad spectrum of diseases, mainly in human inflammatory and autoimmune diseases. In the present study, we examined the effects of prednisone, thalidomide, cyclosporine A, and amitriptyline, drugs used in a variety of clinical conditions, on the production of TNF-α, IL-10, and IL-12 by purified epidermal Langerhans cells and peritoneal macrophages in BALB/c mice.
All drugs inhibited TNF-α production by Langerhans cells after 36 hours of treatment at two different concentrations, while prednisone and thalidomide decreased IL-12 secretion significantly, amitriptyline caused a less pronounced reduction and cyclosporine A had no effect. Additionally, TNF-α and IL-12 production by macrophages decreased, but IL-10 levels were unchanged after all treatments.
Our results demonstrate that these drugs modulate the immune response by regulating pro-inflammatory cytokine production by purified epidermal Langerhans cells and peritoneal macrophages, indicating that these cells are important targets for immunosuppression in various clinical settings.
Available from: Juan Cata
- "The exact mechanism of action is not clear, but modulation of the production and release of TNF-α is thought to be especially important. Thalidomide reduces synthesis of TNF-α, IL-12 and IL-8 in culture of LPSstimulated human monocytes and microglial cells (Lokensgard et al, 2000; Moller et al, 1997; Sampaio et al, 1991; Sampaio et al, 1993). Thalidomide also accelerates the degradation of pro-inflammatory cytokines (Moreira et al, 1993); and dampens their intracellular signaling by inhibiting the translocation of NF-κB into the nucleus (Keifer et al, 2001). "
[Show abstract] [Hide abstract]
ABSTRACT: Chemotherapy-induced pain is the most common treatment-limiting complication encountered by cancer patients receiving taxane-, vinca alkaloid- or platin-based chemotherapy. Several lines of evidence indicate that activation of pro-inflammatory cascades involving the release of cytokines including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and interleukin-6 (IL-6) as well as various growth factors are key events in the pathogenesis of many types of nerve-injury related pain. Similar mechanisms might also be involved in the etiology of chemotherapy-induced pain. Thalidomide and minocycline have profound immunomodulatory actions in addition to their originally intended pharmacological actions. These compounds were evaluated here for effects in preventing the development of taxol-induced mechanical and thermal hyperalgesia in rats. Thalidomide (50.0 mg/kg) reduced taxol-induced mechanical allodynia and hyperalgesia whereas minocycline (20.0 mg/kg) reduced taxol-induced mechanical hyperalgesia and allodynia as well as taxol-induced thermal hyperalgesia. These results suggest that immunomodulatory agents may provide a treatment option for the protection or reversal of chemotherapy-related pain.
Available from: Oliver Goodyear
- "Despite impressive clinical activity it remains uncertain as to exactly how these effects are mediated. Thalidomide certainly has a promiscuous mode of action (Bartlett et al, 2004a) with anti-angiogenic activity, direct effects on myeloma cells, alteration of the cytokine milieu within the bone marrow microenvironment including downregulation of TNF-a (Sampaio et al, 1991), possible modulation of IL-12 and IL-15 production and immunomodulatory properties (Haslett et al, 1997, 1998; Moller et al, 1997 and 2003; Corral et al, 1999; Verbon et al, 2000; Davies et al, 2001). However, the relative importance of these individual activities has not been determined. "
[Show abstract] [Hide abstract]
ABSTRACT: Multiple myeloma is a malignant tumour of plasma cells that remains incurable for the vast majority of patients, with a median survival of 2-3 years. It is characterized by the patchy accumulation of tumour cells within bone marrow leading to variable anaemia, bone destruction, hypercalcaemia, renal failure and infections. Immune dysfunction is an important feature of the disease and leads to infections that are both a major cause of morbidity and mortality and may promote tumour growth and resistance to chemotherapy. Numerous defects of the immune system have been described in multiple myeloma although the relative clinical importance of these remains elusive. There has been considerable interest in the identification of an autologous response against myeloma. Although T cells and humoral responses directed against myeloma-associated antigens have been described, it is uncertain if the immune system plays a role in preventing or controlling myeloma cell growth. There is increasing interest in the potential role of immunotherapy but the success of these interventions is likely to be modified by the immunologically hostile environment associated with multiple myeloma. This review attempts to summarize the current knowledge relating to the immune defects found in multiple myeloma.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.