We have been proposing the functional discrimination of two classes of macrophages (Mp), i.e. reductive macrophages (RMp) with a high intracellular content of glutathione and oxidative macrophages (OMp) with a reduced content. In this paper we will present the evidence that the T(h)1/T(h)2 balance is regulated by the balance between RMp and OMp due to the disparate production of IL-12 versus IL-6 and IL-10. RMp were induced by in vivo application of N-acetyl-L-cysteine or glutathione monoethylester and OMp by L-cystine derivatives, diethyl maleate or L-buthionine-[S,R]-sulfoximine. The Mp arbitrarily called OMp showed elevated IL-6 and IL-10 production, and reduced NO and IL-12 production. The RMp elicited a reciprocal response, i.e. elevated IL-12 and NO production, and reduced IL-6 and IL-10 production. The cytokine propensities of OMp or RMp were inter-converted to each other. The results were also confirmed by using auto-MACS purified F4/80(+) Mp without adherence. Interestingly, IFN-gamma induced RMp and augmented NO generation with decreased production of IL-6, whilst IL-4 induced OMp and augmented IL-6 production. CD4(+)CD44(-) naive T(h)0 cells were differentiated preferentially either to T(h)l or T(h)2 cells, depending on the presence of RMp or OMp during the initial 24 h of culture, from ovalbumin-specific TCR-transgenic mouse spleen cells in the presence of IL-2. Taken together, RMp induction may generate the amplification loop of a RMp/T(h)1 circuit and OMp that of OMp/T(h)2. The findings implicate that the alteration in Mp functions because altered intracellular glutathione may play a relevant role in the pathological progression of inflammation.