Alteration of interleukin-1 activity and the acute phase response in adjuvant arthritic rats treated with disease modifying antirheumatic drugs

Abstract

Interleukin-1 (IL-1) activity and the acute phase response, as measured by plasma CRP and iron, were used to determine if the standard disease modifying antirheumatic drugs (DMARDs), gold, chloroquine and D-penicillamine had a common profile of activity in the adjuvant arthritic (AA) rat. All drugs were tested at a dose which significantly reduced noninjected paw swelling in AA rats. Inhibition of paw edema ranged from 37% for D-penicillamine (100 mg/kg) to 69% for auranofin (10 mg/kg). Two week medication of AA rats with gold sodium thiomalate (GST, 10 mg/kg, i.m.) or auranofin (10 mg/kg, p.o.) resulted in a significant decrease in splenic IL-1 activity, as measured in the standard lymphocyte activating factor (LAF) assay. The acute phase response, often associated with elevated IL-1 activity, was also significantly reduced following treatment of AA rats with 10 mg/kg of GST or auranofin (oral gold). Inhibition of the acute phase response by gold was determined by a significant reduction of plasma CRP levels (56-71% reduction) and enhancement of plasma iron levels (27-52% enhancement). In contrast to the effect of GST and auranofin on IL-1, CRP and iron, treatment with chloroquine (20, 30 and 35 mg/kg) and D-penicillamine (55 and 100 mg/kg) failed to reduce the acute phase response (as measured by plasma CRP and iron) or alter LAF activity from AA rat spleen cell supernatants. Based on its ability to reduce LAF activity in spleen cell supernatants and reduce the acute phase response, it is possible that the activity of gold in the AA rat may in part be due to its ability to inhibit IL-1 production in vivo. The inability of chloroquine and D-penicillamine to alter LAF activity and the acute phase response in AA rats does not preclude their possession of an immunoregulatory mechanism of action, but it does indicate that their mechanism of action in the AA rat probably differs from that of GST and auranofin.

Differential effects of anti-arthritic agents on subnormal plasma iron levels in adjuvant arthritic rats

“…plasma iron depression) is under cytokine control (i.e. IL-I, IL-6, TNF) then the reversal of plasma iron depression by immunosuppressives, glucocorticoids and the gold DMARD's is in keeping with our results showing inhibition of high splenic IL-1 levels by these agents [5,7,9]. It appears that measurement of plasma iron levels in adjuvant arthritic rats may be a means of differentiating between NSAID's and other groups of anti-arthritic compounds.…”

Evaluation of <i>in vitro</i> and <i>in vivo</i> anti-arthritic potential of <i>Berberis calliobotrys</i>

“…Anemia is the most common extracellular manifestation in RA (Hochberg et al, 1988) and may be caused by the decreased level of plasma iron due to sequestration of iron in the reticuloendothelial system and synovial tissue ultimately failure of bone marrow to counter anemia (Mowat, 1971). IL-1 in association with the acute phase response also decrease plasma iron content (Connolly et al, 1988) and it is challenging to speculate that the sequestration of less deformable erythrocytes by endothelial cells in the spleen also plays a causative role in shortened half life of erythrocytes thus, resulting in anemia. Alternatively, a rise in both WBC and platelet counts might be due to the stimulation of immune system against the invading pathogenic microorganism and it is evident by the influx of inflammatory mononuclear cells in the joints of arthritic rats.…”

Modulation of α1-acid glycoprotein (AGP) gene induction following honey bee venom administration to adjuvant arthritic (AA) rats; possible role of AGP on AA development

“…In addition, AGP gene expression is increased during the active phases of disease developmenl. or is significantly reduced when AA is suppressed by several drugs (Figs 1 and 3) [26]. Membrane-bound AGP has been found on normal human lymphocytes, granulocytes and monoeytes [3].…”

“…Since we were not able to determine the scrum IL-1 activity using the thymocyte coslimulaiory assay [26]. we determined by in situ hybridization the IL-la mRNA producing peritoneal macrophages isolated from HBV-trcatcd and untreated normal or AA rats.…”