Using IL-6-deficient (IL-6 -/-) or wild-type mice, we investigated whether IL-6 is involved in the intestinal adjuvant activity of cholera toxin (CT) and to what extent IL-6 is required for mucosal IgA responses against soluble protein Ags or live Helicobacter felis infection. In naive IL-6 -/- mice we found normal total IgA levels in serum, bronchial and intestinal lavage and unaltered frequencies of IgA plasma cells in intestinal lamina propria. In Peyer's patches (PP) and mesenteric lymph nodes (MLN) IgA-producing cells were as frequent in IL-6 -/- as in wild-type mice. Immunohistochemical analysis of PP revealed germinal centers that co-localized IgA+ cells, indicating B cell activation and isotype switching in situ in the intestinal immune inductive site. Phenotypic analysis of the distribution of conventional B-2 cells (B220+CD5-/Mac-1-) and B-1 cells (B220+, CD5+/Mac-1+) in intestine-associated tissues gave comparable results in IL-6 -/- and wild-type mice. The ability to respond with mucosal IgA following oral and intranasal immunization with specific Ag, KLH or OVA, in the presence of CT adjuvant or to live H. felis infection was similar in IL-6 -/- and wild-type mice. CT exerted strong and comparable adjuvant functions in IL-6 -/- and wild-type mice. Repeated oral immunizations with CT alone stimulated immune protection against CT-induced diarrhea in ligated loops that was of similar magnitude in IL-6 -/- and wild-type mice. We conclude that, although IL-6 has been ascribed a crucial role in terminal differentiation of IgA B cells in vitro, we found no evidence to support the notion that IL-6 is critically required for IgA B cell development or specific mucosal IgA responses in vivo.