Aberrant macrophage cytokine production is a conserved feature among autoimmune-prone mouse strains - Elevated interleukin (IL)-12 and an imbalance in tumor necrosis factor-alpha and IL-10 define a unique cytokine profile inmacrophages from young nonobese diabetic mice

Cytokines derived from macrophages (M phi) play a critical role in the deve lopment of type 1 diabetes in the nonobese diabetic (NOD) mouse. Based on e arlier findings from lupus-prone strains of inherent cytokine defects in M phi, NOD M phi were evaluated for intrinsically dysregulated cytokine produ ction with the potential to initiate or exacerbate disease. Endotoxin-activ ated peritoneal M phi from young prediseased NOD mice produced interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha levels similar to those of M p hi from a panel of control strains but reduced compared with the congenic d iabetes-resistant NOR strain. IL-6 and IL-10 production were similar in NOD and NOR M phi, indicating that reduction in NOD IL-1 and TNF-alpha express ion was selective. Nevertheless, the ratio of TNF-alpha and IL-10 productio n, a stringent index of normal M phi function, distinguished NOD from all n ormal strains. The most striking feature of NOD M phi, however, was their s ubstantially elevated IL-12 production. This response was induced not only by endotoxin but also by bacillus Calmette-Guerin (BCG) and CD40 ligand and was associated with land likely caused by) the enhanced and prolonged expr ession of p40 mRNA. Moreover, NOD M phi IL-12 expression appeared to be nea r maximally induced by lipopolysaccharide (LPS) alone, because it was only slightly enhanced by the addition of gamma-interferon, a stimulus that subs tantially elevated LPS-induced IL-12 production in M phi from normal strain s. Accompanied by a unique profile of TNF-alpha and IL-10, the dramatic ele vation of IL-12 expression by NOD M phi reflects intrinsic defects of the i nnate immune system with the potential to initiate and propagate the pathog enic autoreactive T-helper type 1 response characteristic of type 1 diabete s.