Immunopharmacology
-
Case Reports Comparative Study
Comparative study of lymphocyte-suppressive potency between prednisolone and methylprednisolone in rheumatoid arthritis.
We compared lymphocyte-suppressive potencies of prednisolone and methylprednisolone in rheumatoid arthritis (RA). IC(50)s of the glucocorticoids (GCs) on concanavalin A-induced blastogenesis of peripheral-blood mononuclear cells (PBMCs) from 44 RA patients and 30 healthy subjects were estimated in vitro, and differences in the IC(50)s of the two GCs were evaluated. The mean (+/-SD) IC(50)s for prednisolone and methylprednisolone on PBMC-blastogenesis of RA were 17.2+/-17.1 and 12.6+/-18.4 ng/ml, respectively, and no significant differences were observed between prednisolone-IC(50) and methylprednisolone-IC(50). ⋯ In prednisolone-IC(50), however, such differences between the two patient-subgroups were not observed. Unlike reported cases of renal transplantation and healthy subjects, there was no difference in the lymphocyte-suppressive potencies for both prednisolone and methylprednisolone on RA-PBMCs. However, PBMCs from RA patients exhibiting high levels of RF or RAPA are more sensitive to methylprednisolone rather than prednisolone.
-
The Randall-Selitto paradigm (maximal tolerated pressure externally applied by a mechanical device) was used to develop a rat model of localized inflammatory hyperalgesia in order to compare the analgesic effects of bradykinin (BK) B1 and B2 receptor antagonists and of a non-steroidal anti-inflammatory drug (NSAID). Intra-plantar injection of zymosan (12.5 mg per paw) induced a considerable inflammation as evidenced from gross and histological evaluation and a mechanical hyperalgesia at 6 h. The contra-lateral paw of zymosan-treated animals or saline vehicle-injected paws did not exhibit a decreased pressure tolerance, relative to pre-injection measurements. ⋯ The kinin B1 receptor antagonists [Leu8]des-Arg9-BK (3-30 nmol/kg) and R-715 (100 nmol/kg), the B2 receptor antagonists Hoe 140 (15 nmol/kg) and LF 16.0687 (3 and 10 mg/kg), as well as the NSAID diclofenac sodium (1 and 3 mg/kg) significantly reversed zymosan-induced hyperalgesia. We conclude that zymosan-induced hyperalgesia is a model suitable for the rapid evaluation of analgesic drugs with a peripheral site of action interfering either with kinin receptors or with prostanoid formation. In this regard, results of the present study confirm that blocking kinin B1 receptors is a novel approach for treatment of inflammatory pain.
-
Angioedema (AE) associated with angiotensin-converting enzyme inhibitors (ACEi) is a rare, but potentially life-threatening adverse reaction. Several studies have suggested that bradykinin (BK) is responsible for ACEi-induced AE, but the mechanism remains unclear. We investigated the metabolism of BK and des-Arg9-BK in the serum of 20 patients with a history of ACEi-associated AE and 21 control (C) subjects. ⋯ However, a test dilution of AE + sera with a control (C) serum showed that an enzyme defect rather than a circulating inhibitor could be responsible for the abnormal metabolism of des-Arg9-BK when ACE is inhibited. In conclusion, half of the patients with ACEi-associated AE present in serum had an enzyme defect involved in the des-Arg9-BK metabolism leading to its accumulation. The B1 agonist could be responsible, at least in part, for the local inflammatory reaction associated with the AE.
-
In murine models of experimental endotoxemia, inflammatory cytokines as well as antiinflammatory interleukin-10 (IL-10) appear in the circulation after the injection of lipopolysaccharide (LPS). There is considerable experimental evidence to suggest that the major function of endogenously produced IL-10 is to down-regulate inflammatory cytokine production. Indeed, the protective effects of exogenously administered IL-10 against murine endotoxin lethality have been shown to correlate with its ability to inhibit the LPS-induced production of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). ⋯ We show that pretreatment with a neutralizing anti-mouse IL-10 monoclonal antibody (mAb) has no effect on the ability of rhuIL-10 to suppress an LPS-induced inflammatory cytokine response in these mice. In contrast, the suppressive effects of the human protein on inflammatory cytokine responses are blocked completely by pretreating the animals with an anti-huIL-10 mAb. These data show that despite the up-regulated endogenous IL-10 response, it is the exogenously administered rhuIL-10 that is directly responsible for the suppressed inflammatory cytokine responses that are observed when the human protein is given to endotoxemic mice.
-
We recently demonstrated that calprotectin, an abundant calcium-binding protein complex in polymorphonuclear leukocytes (PMNs), has the capacity to induce growth inhibition and apoptotic cell death against a variety of tumor cell lines and normal cells such as fibroblasts. Therefore, calprotectin which is released to extracellular spaces, might cause tissue destruction in severe inflammatory conditions. In search of drugs to suppress the cytotoxic effects of calprotectin, we screened plant products that have been used as Chinese medicines. ⋯ Since we previously showed that target protein synthesis is necessary for induction of cell death and that calprotectin actually upregulates the net protein synthesis of MM46 cells, we compared the dose-response relationship between the inhibitory effects of lycorine on calprotectin action and target protein synthesis. Although 1 microg/ml lycorine did not bring about marked inhibition of protein synthesis in MM46 cells without calprotectin, it attenuated the protein synthesis that was augmented by calprotectin to the level of protein synthesis in cells not treated with calprotectin. These results suggest that lycorine inhibition for calprotectin cytotoxicity is not solely due to its inhibitory effect on protein synthesis.