Inflammatory fibrosis is a characteristic feature of myocarditis, dilated cardiomyopathy (DCM), and congestive heart failure. Th1-type immune responses, mediated by interleukin (IL)-12-induced interferon (IFN)-gamma, are believed to exacerbate autoimmune diseases including myocarditis. In this study, we examined the effect of IL-12R beta 1 and IFN-gamma deficiency on the development of chronic CB3-induced myocarditis using knockout mice. We found increased chronic CB3-induced myocarditis (14.1 to 43.1%, P < 0.001); pericarditis (1.5 to 7.6%, P < 0.001); fibrosis (9.7 to 27.4%, P < 0.05); and the profibrotic cytokines transforming growth factor-beta(1), IL-1 beta, and IL-4 in the hearts of IFN-gamma-deficient mice. All mice infected with CB3 developed DCM, but IFN-gamma-deficient mice developed a fibrous, adhesive pericarditis associated with increased numbers of degranulating mast cells (MCs) in the pericardium (26.6 to 45.9%, P < 0.01), increased histamine levels (716 to 1930 ng/g of heart, P < 0.01), and reduced survival (100 to 43%). In contrast, IL-12R beta 1 deficiency did not significantly alter the development of chronic myocarditis. Thus, IFN-gamma protects against the development of severe chronic myocarditis, pericarditis, and DCM after CB3 infection by reducing MC degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-beta(1), IL-1 beta, and IL-4 in the heart.
The development of opioid-induced analgesic tolerance and hyperalgesia is a clinical challenge for managing chronic pain. Adaptive changes in protein translation in the nervous system are thought to promote opioid tolerance and hyperalgesia; however, how opioids drive such changes remains elusive. Here, we report that mammalian target of rapamycin (mTOR), which governs most protein translation, was activated in rat spinal dorsal horn neurons after repeated intrathecal morphine injections. Activation was triggered through μ opioid receptor and mediated by intracellular PI3K/Akt. Spinal mTOR inhibition blocked both induction and maintenance of morphine tolerance and hyperalgesia, without affecting basal pain perception or locomotor functions. These effects were attributed to the attenuation of morphine-induced increases in translation initiation activity, nascent protein synthesis, and expression of some known key tolerance-associated proteins, including neuronal NOS (nNOS), in dorsal horn. Moreover, elevating spinal mTOR activity by knocking down the mTOR-negative regulator TSC2 reduced morphine analgesia, produced pain hypersensitivity, and increased spinal nNOS expression. Our findings implicate the μ opioid receptor-triggered PI3K/Akt/mTOR pathway in promoting morphine-induced spinal protein translation changes and associated morphine tolerance and hyperalgesia. These data suggest that mTOR inhibitors could be explored for prevention and/or reduction of opioid tolerance in chronic pain management. IntroductionChronic pain is a major public health problem. About 116 million Americans (approximately 30% of the population) live with this disorder. The economic impact of chronic pain is equally large, at around $100 billion annually (1). Although recent advances have been made in the therapeutic management of chronic pain, opioids are still the gold standard for its pharmacological treatment in the clinical setting. However, long-term use of these drugs is often limited by the development of analgesic tolerance and hyperalgesia, phenomena observed in both laboratory animals and patients (2). Opioid tolerance is characterized by a progressive lack of response to opioids that can be overcome by escalating doses to achieve equivalent pain relief. In contrast, opioid-induced hyperalgesia is a sensitization process in which opioids paradoxically produce pain hypersensitivity. These undesirable manifestations, along with other adverse effects caused by escalating doses (e.g., oversedation, respiratory depression, and constipation), significantly decrease quality of life in patients with chronic pain.Despite intensive research into the neurobiological mechanisms of opioid-induced tolerance and hyperalgesia in the past decades, opioid-induced tolerance and hyperalgesia are still ineffectively managed by current drugs, in part because these drugs target a single mechanism and/or produce several side effects. It is well docu-
Autoimmune diseases can be reduced or even prevented if proinflammatory immune responses are appropriately down-regulated. Receptors (such as CTLA-4), cytokines (such as TGF-β), and specialized cells (such as CD4+CD25+ T regulatory cells) work together to keep immune responses in check. T cell Ig mucin (Tim) family proteins are key regulators of inflammation, providing an inhibitory signal that dampens proinflammatory responses and thereby reducing autoimmune and allergic responses. We show in this study that reducing Tim-3 signaling during the innate immune response to viral infection in BALB/c mice reduces CD80 costimulatory molecule expression on mast cells and macrophages and reduces innate CTLA-4 levels in CD4+ T cells, resulting in decreased T regulatory cell populations and increased inflammatory heart disease. These results indicate that regulation of inflammation in the heart begins during innate immunity and that Tim-3 signaling on cells of the innate immune system critically influences regulation of the adaptive immune response.
The development of autoimmune disease involves a combination of genetic and environmental factors. Many autoimmune diseases are believed to be triggered by viral infections. Since the early, natural immune response to infection can determine the later development of the adaptive immune response, innate immunity likely influences the progression from viral immunity to autoimmunity. To investigate the role of the innate immune response on susceptibility to autoimmune disease, we compared the early cytokine response of mice susceptible or resistant to the development of autoimmune heart disease following viral infection. We found that susceptible BALB/c mice produced elevated levels of TNF-alpha, IL-1beta, and IL-4 within hours of Coxsackievirus B3 (CB3) infection. These cytokines are known to be critical for the development of autoimmune heart disease, and are also rapidly produced from activated mast cells (MC). Degranulating MC were observed as early as 6 h following CB3 infection in the heart, and significantly higher numbers of MC were found in the spleen of susceptible BALB/c mice at this time. Thus, susceptibility to autoimmune heart disease can be determined as early as 6 h following viral infection in susceptible strains of mice.
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