Interleukin-10 in murine metal-induced systemic autoimmunity

Systemic autoimmune diseases have a complicated and largely unknown aetiology and pathogenesis, but they are at least partly obeying the rules of an ordinary immune response. Cytokines are therefore important in the pathogenesis as demonstrated by the recent success in treating rheumatoid arthritis with anti-cytokine agents. The suppressive functions in the immune system have lately received much interest. One of the cytokines in focus in this respect is interleukin (IL)-10. We recently observed that in heavy-metal induced systemic autoimmunity, genetically resistant mice show a strong increase in IL-10 mRNA expression, which was not seen in susceptible mice. We have therefore examined the possible regulating effect of IL-10 on the induction and manifestation of systemic autoimmunity in this model. We took two approaches: a targeted mutation of the IL-10 gene in a strain resistant to heavy metal-induced autoimmunity, and treatment with recombinant IL-10 in the genetically susceptible A.SW strain during the induction of autoimmunity by metals. The wild-type C57BL/6 J (B6-WT) strain did not react with lymphoproliferation, polyclonal B cell activation, anti-nucleoar autoantibodies (ANoA) or tissue immune-complex (IC) deposits in response to inorganic mercury (Hg) or silver (Ag). However, serum IgG1 and IgE showed a modest increase during Hg treatment, while Ag caused a weak increase in IgE and IgG2a. The B6.129P2-Il10(tm1Cgn)/J strain (IL-10-deficient mice) did not develop antinucleolar antibodies (ANoA) during Hg treatment, but showed a higher median titre of homogeneous ANA compared with Hg-treated B6-WT mice. Both control and Hg-treated (but not Ag-treated) IL-10-deficient mice showed an increase in splenic weight and serum IgG1 compared with B6-WT control and Hg-treated mice. An early, significant increase in serum IgE was seen in Hg-treated IL-10-deficient and WT mice compared with the controls; the increase was 42- and sixfold, respectively. During ongoing intense treatment with rIL-10 in combination with Hg the susceptible A.SW mice showed a reduced development of ANoA and antichromatin antibodies, as well as serum IgE, compared with mice receiving Hg but not rIL-10. In conclusion, IL-10 suppresses several aspects of HgIA, but is not crucial for resistance to heavy metal-induced autoimmunity. Peroral silver treatment suppresses the spontaneous immune activation seen in IL-10-deficient mice.