B10.RIII and B10.G mice were transferred from a diet of laboratory rodent chow to a standard diet in which all the fat (5% by weight) was supplied as either fish oil (17% eicosapentaenoic acid [EPA], 12% docosahexaenoic acid [DHA], 0% arachidonic acid [AA], and 2% linoleic acid) or corn oil (0% EPA, 0% DHA, 0% AA, and 65% linoleic acid). The fatty acid composition of the macrophage phospholipids from mice on the chow diet was similar to that of mice on a corn oil diet. Mice fed the fish oil diet for only 1 wk showed substantial increases in macrophage phospholipid levels of the omega-3 fatty acids (of total fatty acid 4% was EPA, 10% docosapentaenoic acid [DPA], and 10% DHA), and decreases in omega-6 fatty acids (12% was AA, 2% docosatetraenoic acid [DTA], and 4% linoleic acid) compared to corn oil-fed mice (0% EPA, 0% DPA, 6% DHA, 20% AA, 9% DTA, and 8% linoleic acid). After 5 wk this difference between the fish oil-fed and corn oil-fed mice was even more pronounced. Further small changes occurred at 5-9 wk. We studied the prostaglandin (PG) and thromboxane (TX) profile of macrophages prepared from mice fed the two diets just before being immunized with collagen. Irrespective of diet, macrophages prepared from female mice and incubated for 24 h had significantly more PG and TX in the medium than similarly prepared macrophages from male mice. The increased percentage of EPA and decreased percentage of AA in the phospholipids of the macrophages prepared from the fish oil-fed mice was reflected in a reduction in the amount of PGE2 and PGI2 in the medium relative to identically incubated macrophages prepared from corn oil-fed mice. When this same fish oil diet was fed to B10.RIII mice for 26 d before immunization with type II collagen, the time of onset of arthritis was increased, and the incidence and severity of arthritis was reduced compared to arthritis induced in corn oil-fed mice. The females, especially those on the fish oil diet, tended to have less arthritis than the males. These alterations in the fatty acid pool available for PG and leukotriene synthesis suggest a pivotal role for the macrophage and PG in the immune and/or inflammatory response to type II collagen.

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Plasma concentrations of 25-hydroxyvitamin D3 (25-OHD3) and 1 alpha,25-dihydroxyvitamin D3 (1 alpha, 25-(OH)2D3) in growing chicks and weanling rats were measured by a new radioreceptor assay to determine the effects of varying dietary levels of vitamin D3. The plasma concentration of 25-OHD3 fell from 14.1 ng/ml in 1-day-old chicks to undetectable levels after 3 weeks on a rachitogenic diet. Circulating 1 alpha,25-(OH)2D3 hormone also decreased from 8.9 ng/100 ml to undetectable levels at 3 weeks in these chicks. Chicks receiving an optimal supplement of vitamin D3 (1.4 IU/g diet) for three to four weeks had plasma 25-OHD3 and 1 alpha,25-(OH)2D3 levels of 21-35 ng/ml and 5.1-7.5 ng/100 ml, respectively. Nutritional supplementation with a 50-fold excess of vitamin D3 (70 IU/g diet) elicited a substantial increase in plasma 25-OHD3 to 87-130 ng/ml, while plasma 1 alpha,25-(OH)2D3 was not increased. Increasing dietary calcium from 1.4 to 2.8% did not alter the circulating level of vitamin D3 metabolites in chicks fed 1.4 IU of vitamin D3/g diet. Direct measurement of the renal 25-OHD3-1 alpha-hydroxylase in vitro, showed that lowering dietary calcium or exclusion of vitamin D3 stimulated the biosynthesis of 1 alpha,25-(OH)2D3, but raising calcium did not alter the enzyme activity. It is concluded that the circulating concentration of the 1 alpha,25-(OH)2D3 hormone in the chick is unaffected by abnormally high intakes of vitamin D3 or calcium, but the renal production of the hormone increases during vitamin D3 or calcium deprivation. Additional studies in rats fed a diet supplemented with either 2 or 1000 IU of vitamin D3/g verify that the circulating concentration of 25-OHD3 is markedly increased when the dietary intake of vitamin D3 is elevated. Moreover, 1 alpha,25(OH)2D3 is not increased under these conditions, but actually falls significantly when the dietary level of vitamin D3 is raised from 2 to 1000 IU/g. These studies in both the chick and rat indicate that dietary vitamin D3 excess enhances circulating 25-OHD3, probably because the vitamin D3-25-hydroxylase enzyme is not strigently controlled. The fact that the circulating 1 alpha,25-(OH)2D3 is not concomitantly increased may reflect either decreased synthesis or increased utilization of the 1 alpha,25-(OH)2D3 sterol.