We have analysed separately the role of B‐cell receptor (BCR) stimulation and the soluble second signal in the T‐cell‐independent type 2 (TI‐2) B‐cell response. We were able to show that human B cells and macrophages (Mφ) could function together in TI‐type microbial response. Interestingly, BCR cross‐linking of peripheral blood (PB) B cells enhanced IgG production induced by Mφ‐derived growth factors whereas interleukin (IL)‐12 + IL‐18 had milder effect on IgG production. We demonstrated that B‐cell‐derived soluble mediators primed lipopolysaccharide (LPS)‐stimulated Mφ for tumour necrosis factor‐α (TNF‐α) and IL‐6 production significantly better than IFN‐γ, confirming the role of B cells in the activation of Mφ. We could show that human PB B cells were active cytokine producers and could be induced to produce interferon (IFN)‐γ mRNA in the presence of known Mφ cytokines, like IL‐12 and IL‐18. BCR stimulation also stabilized and enhanced the IFN‐γ mRNA production induced by IL‐12 and IL‐18. In addition, our novel finding was that a known Mφ cytokine, IL‐10, induced the expression of IFN‐γ mRNA from human B‐cell line (HF28R0) cells. In summary, we propose a model for the active role of B cells in the induction of the inflammatory response during TI antigen challenge in close collaboration with Mφ.