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The effects of four commercial strains of Streptococcus thermophilus used in yogurt manufacturing on cytokine production were evaluated by using a macrophage model (RAW 264.7 cells) and a T-helper-cell model (EL4.IL-2 thymoma cells) and compared to immunologically active strains of Lactobacillus bulgaricus, Bifidobacterium adolescentis, and Bifidobacterium bifidum. All cytokines (TNF-alpha and IL-6 in RAW 264.7 cells and IL-2 and IL-5 in EL4.IL-2 cells) were affected by heat-killed S. thermophilus in a strain- and dose-dependent fashion. Organisms of all three genera induced significant increases in IL-6 production by the macrophage line ranging from 31- to 192-fold, with S. thermophilus St 133 showing the greatest activity. The four S. thermophilus strains also strongly induced TNF-alpha production (from 135- to 176-fold). IL-6 and, to a lesser extent, TNF-alpha production were also increased when the macrophages were costimulated with lipopolysaccharide and cells of the three groups of lactic acid bacteria. Upon concurrent stimulation of EL4.IL-2 cells with phorbol 12-myristate-13-acetate, seven of the eight strains displayed significant enhancement of IL-2 and IL-5 production, with S. thermophilus being most effective. Taken together, the S. thermophilus strains stimulated macrophage and T-cell cytokine production to a similar or greater extent than did the species of Bifidobacterium and Lactobacillus. These and previous results lend further support to the contention that lactic acid bacteria, in a concentration-dependent manner, can differentially induce cytokine production in macrophages, but that the effects on T cells required a costimulatory signal and were less remarkable.

When used in commercial fermented dairy products, bifidobacteria may enhance immunity by stimulating cytokine secretion by leukocytes. To assess whether interaction between bifidobacteria and leukocytes promote cytokine production, we cultured RAW 264.7 cells (macrophage model) and EL-4.IL-2 thymoma cells (helper T-cell model) in the presence of 14 representative strains of heat-killed bifidobacteria. In unstimulated RAW 264.7 cells, all bifidobacteria induced pronounced increases (up to several hundred-fold) in the production of tumor necrosis factor-alpha compared with that of controls. Interleukin-6 production by unstimulated cells also increased significantly, but less than did tumor necrosis factor-alpha. Upon concurrent stimulation of RAW 264.7 cells with lipopolysaccharide, production of tumor necrosis factor-alpha and interleukin-6 were both enhanced between 1.5- to 5.8-fold and 4.7- to 7.9-fold, respectively, when cultured with 10(8) bifidobacteria/ml. In unstimulated EL-4.IL-2 cells, bifidobacteria had no effect on the production of interleukin-2 or interleukin-5. Upon stimulation of EL-4.IL-2 with phorbol-12-myristate-13-acetate, there were variable increases in interleukin-2 secretion (up to 2.4-fold for 10(6) Bifidobacterium Bf-1/ml) and interleukin-5 secretion (up to 4.6-fold for 10(8) B. adolescentis M101-4). The results indicated that, even when variations among strains were considered, direct interaction of most bifidobacteria with macrophages enhanced cytokine production, but the effects on cytokine production by the T-cell model were less marked. Interestingly, the 4 bifidobacteria strains used commercially for diary foods showed the greatest capacity for cytokine stimulation. The in vitro approaches employed here should be useful in future characterization of the effects of bifidobacteria on gastrointestinal and systemic immunity.