Scand. J. Immunol. 3t, 335-343, 1990 Ciclosporin-Dependent, «w-Independent, Mucosal Interleukin 6 Response to Gram-Negative Bacteria S. HEDGES, H. LINDER, P. DE MAN & C. SVANBORG EDEN Department of Clinical Immunology, University of Goteborg, Sweden Hedges, S., Linder, H., de Man, P. & Svanborg Eden, C. Ciclosporin-Dependent, nu- Independent, Mucosal Interleukin 6 Response to Gram-Negative Bacteria. Scand. J. Immunol. 3t, 335-343, 1990 Regulation of the mucosal inflammatory response to Gram-negative bacteria was analysed. The interleukin 6 (IL-6) secretion, influx of polymorphonuclear leucocytes into urine, and bacterial clearance from the kidneys were compared between Balb/c (nu/nu) and ««/+ mice, with and without ciclosporin (CsA) treatment. There was no significant influence ofthe nu genotype on any ofthe host responses measured. CsA pretreatment significantly decreased 11-6 secretion in both nu/nu and nu/ ± mice, but did not aflect bacterial clearance or the leucocyte response in any mouse strain tested. Tissue damage, in addition to bacterial infection, resulted in significantly higher levels of IL-6 than bacterial infection alone. Tissue-damaged mice were significantly less likely to clear the bacterial infection than their non-damaged counterparts, but there was no significant difference in the leucocyte response. CsA pretreatment did not significantly reduce the levels of IL-6 in the tissue-damaged mice. These results demonstrate that the mucosal inflammatory response to Gram-negative infection, including IL-6 secretion, is nw-independent, and that bacterial infection alone or in combination with tissue damage induce IL-6 secretion by two different pathways. S. Hedges, Department of Clinical Immunology, University of Goteborg, Gulhedsgatan 10, Goteborg, Sweden Mucosal challenge with Gram-negative bacteria induces the secretion of interleukin-6 (IL-6) [5]. IL-6 can be produced by a wide variety of cells including lymphocytes and monocytes [1, 13]. In this model the epithelial cells have been proposed as the originators of urinary IL-6. Renal tubule cells in culture secrete IL-6 in response to bac- terial challenge (S. Hedges et al., manuscript in preparation). T lymphocytes influence epithelial cell functions [14, 25] and other aspects of mucosal immunity such as the differentiation of B lymphocytes to IgA-producing plasma cells [18]. The role of T lymphocytes in the regulation of mucosal IL-6 has not been evaluated however. In addition to IL-6 production. Gram-negative infection results in the recruitment of polymor- phonuclear leucocytes (PMN) to the mucosal site. This inflammatory response coincides with the elimination of bacteria. Infection persists in mice unable to mount an inflammatory response due either to a defective ips locus [28] or to treatment with anti-inflammatory agents [17]. Previous studies have provided conflicting evidence regarding the influence of T cells on bacterial clearance from mucosal sites. Nude mice cleared Fseheriehia coli from the urinary tract [26], while ciclosporin (CsA) decreased bacterial clearance from rat kidneys and mouse lung [20, 21]. Although evidence exists both for [19] and against [8] CsA inhibition of accessory cells, CsA has been proposed to exert its immunosuppressive effects mainly through inhibition of T-lympho- cyte functions such as lymphokine production [4], and cytotoxic T-cell activation [22]. CsA can also affect other cell activities however; T-cell re- sponses to type 2 T-independent antigens such as bacterial polysaccharides are CsA-sensitive, while the population responding to type 1 T- independent antigens is CsA-resistant [15]. The aim ofthe present study was to analyse the influence of T-dependent immune mechanisms on IL-6 response, inflammation at mucosal sites, and bacterial clearance from mucosal sites. MATERIALS AND METHODS Mice. C3H/HeN (original breeding stock; Charles River Laboratories, Margate, Kent, UK) mice were 335