Effects of interleukin 12 on immune responses and host protection in mice infected with intestinal nematode parasites.

Abstract

SummaryThe cytokine interleukin (IL) 12 stimulates T cell and natural killer cell production of interferon (IFN) 3' and inhibits T cell production of IL-4. We investigated the effects of IL-12 on cytokine gene expression, immunoglobulin (Ig)E, mucosal mast cell, and eosinophil responses, and the course of infection in mice inoculated with the nematode parasite Nippostrongylus brasiliensis, as well as the IFN-3" dependence of these effects. IL-12 stimulated IFN-3' and IL-10 gene expression during primary and secondary N. brasiliensis infections and inhibited IL-3, IL-4, IL-5, and IL-9 gene expression during primary infections but had little inhibitory effect during secondary infections. IL-12 inhibited IgE, mucosal mast cell, and blood and tissue eosinophil responses during primary infections, but only eosinophil responses during secondary infections. IL-12 enhanced adult worm survival and egg production during primary, but not secondary infections. IL-12 needed to be administered by day 4 of a primary infection to inhibit IgE and mucosal mast cell responses, and by day 6 to strongly inhibit eosinophil responses and to enhance worm survival and fecundity. Anti-IFN-3" mAb inhibited the effects of IL-12 on IgE secretion, intestinal mucosal mastocytosis, and parasite survival and fecundity, but did not affect IL-12 inhibition of eosinophilia. These observations indicate that IL-12, if administered during the initiation of an immune response, can change the response from one that is characterized by the production of T helper (Th)2-associated cytokines to one characterized by the production of Th-1 associated cytokines. However, IL-12 treatment has less of an effect once the production of Th2-associated cytokines has become established. In addition, our results provide evidence that Th2-associated responses protect against, and/or Thl-associated responses exacerbate, nematode infections.

Systemic interleukin 12 displays anti-tumour activity in the mouse central nervous system

“…It has been reported that in vivo treatment of IL-12 increases in both IFN-y and IL-1O mRNA and that the presence of IL-12 results in an efficient priming of the clones for high production of both IFN-y and IL-10 (Finkelman et al, 1994;Gerosa et al, 1996). In the present study, both IFN-y and IL-10 production elevated on days 4 and 6 in the CLN from IL-12 treated MG mice ( Figure 6D).…”

Interleukin‐12 as a target for modulation of the inflammatory response in asthma

“…Interestingly, they demonstrated that while antigen-induced airway eosinophilia is largely IFN-y-independent when IL-12 is given during secondary allergen exposure, when it is given before sensitization, BAL eosinophilia is IFN-y dependent (47). A similar finding was reported in mice infected with the nematode Nippostrongylus brasiliensis, where anti-IFN-y mAb did not affect IL-12-induced inhibition of eosinophilia during a secondary infection (38). Collectively, these studies suggest that IL-12 may either directly suppress eosinophil production or recruitment, or stimulate production of mediators other than IFN-y that have these effects.…”

“…Administration of IL-12 before infection in vivo has been shown to suppress the expression of Th2 cytokines and their associated responses, including eosinophilia, serum IgE, and mucosal mastocytosis, in models of parasitic infection (38,39). In several of these infectious models, exogenous administration of IL-12 exerts considerably less activity when given after the initial stage of host-parasite interaction (35,40).…”

“…Recent in vivo studies in murine models of immune activation (37) and parasite infection (38,39) have shown that IL-12 has tremendous potential as an immunomodulator of Th2 immune responses. Administration of IL-12 before infection in vivo has been shown to suppress the expression of Th2 cytokines and their associated responses, including eosinophilia, serum IgE, and mucosal mastocytosis, in models of parasitic infection (38,39).…”

Inability of IL-12 to Down-Regulate IgE Synthesis Due to Defective Production of IFN-γ in Atopic NC/Nga Mice

“…The fact that the inherited IL-12 and IL-12R deficiencies were found in patients suffering from severe, idiopathic, and disseminated or recurrent mycobacterial or bacterial infection (22)(23)(24)(25) has confirmed an important and indispensable role of IL-12 in acquisition of the resistance to microbial infection through the initiation of the Th1 response. In addition to the induction of Th1, IL-12 is capable of abolishing IgE production in mice immunized with ragweed Ag with aluminum hydroxide (26), infected with intestinal nematode parasites (27), and injected with anti-IgD Ab (28), by inhibition of Th2 responses. On the basis of biological functions of IL-12, preventive or therapeutic trials were performed on several diseases: intracellular microbial infections (16,18,29,30), autoimmune encephalomyelitis (31), allergic airway inflammation (26,32), tumors (33), and Ag-specific tolerance of contact sensitivity (34).…”