Autocrine and Exocrine Regulation of Interleukin-10 Production in THP-1 Cells Stimulated withBorrelia burgdorferiLipoproteins

Abstract

We have recently demonstrated that interleukin-10 (IL-10), produced by THP-1 monocytes in response to Borrelia burgdorferi lipoproteins, dampens the production of concomitantly elicited inflammatory cytokines. Thus, IL-10 could potentially down-regulate inflammatory and microbicidal effector mechanisms of the innate immune response to a B. burgdorferi infection, facilitating the establishment of the spirochete. To understand the mechanism(s) implicated in the regulation of the synthesis and release of IL-10 during early infection, we investigated the autocrine effects of IL-6, IL-12, tumor necrosis factor alpha (TNF-␣), and IL-10 itself, as well as the exocrine effect of IFN-␥ on the production of macrophage-derived IL-10 with lipoprotein as a stimulant. In addition, in view of the differences in the receptor and signal transduction pathways of lipopolysaccharide (LPS) and bacterial lipoproteins, we also investigated the effects described above with LPS as a stimulant. Borrelia burgdorferi, the spirochete that causes Lyme disease, is spread to humans and other mammals through the bite of infected Ixodes ticks (7). Infection may involve multiple organs (3, 42) and may persist in certain tissues for prolonged periods of time (35,48). Spirochetal persistence in the tissues has been associated with severe pathology (9, 16, 48) and both acute and chronic inflammatory conditions (37, 42). B. burgdorferi lacks lipopolysaccharide (LPS) (43), but its genome contains no fewer than 150 genes coding for putative lipoproteins (18); this amounts roughly to 11% of its genome coding capacity. Lipoproteins can directly elicit inflammatory responses both in vitro and in vivo (20,36,38,39,47). Recent findings that lipoproteins can elicit not only inflammatory but also antiinflammatory mediators (e.g., interleukin-10 [IL-10]) from mononuclear cells present in peripheral blood (21, 22) and synovial fluid (49) have added support to the contention that lipoproteins play a crucial role in Lyme disease pathogenesis.One of the hallmarks of Lyme disease is arthritis. This form of the disease has been studied extensively in the mouse model, with an emphasis on the role of cytokines in its etiology. Infection of different inbred mouse strains with B. burgdorferi results in distinct disease outcomes (2,32,48). B. burgdorferi infection elicits severe arthritis in C3H/HeN mice, but mild arthritis in C57BL/6N mice, although both strains harbor similar numbers of spirochetes in their ankles (32). These findings indicate that C57BL/6N mice either produce less proinflammatory cytokines or are better able to regulate inflammation in response to B. burgdorferi lipoproteins than C3H/HeN mice, resulting in a less intense inflammatory response and decreased arthritis severity. Recently, Brown and colleagues (6) corroborated this hypothesis by showing that macrophages from C57BL/6N mice, when stimulated with the lipoprotein outer surface protein A (OspA) or LPS, secreted significantly less proinflammatory cytokines (IL-6 and tumor necrosis factor alpha ...

Lipoproteins, Not Lipopolysaccharide, Are the Key Mediators of the Proinflammatory Response Elicited by Heat-Killed Brucella abortus

“…In addition, we have demonstrated that bacterial lipoproteins also can elicit the production of IL-10, an anti-inflammatory cytokine, in both human and monkey monocytes (29). Both autocrine and exocrine inhibition of IL-10 production resulted in an increase in the production of the proinflammatory cytokines IL-6 and IL-12 (30). The findings that lipoproteins can elicit not only inflammatory, but also anti-inflammatory mediators, e.g., IL-10 from monocytes, have added support to the contention that lipoproteins are crucial factors in the pathogenesis of bacterial infections.…”

Role of Interleukin 10 during Persistent Infection with the Relapsing Fever Spirochete Borrelia turicatae

“…In mice, cultured monocytes from C3H/HeJ mice, which are more susceptible to Lyme arthritis, produced lower amounts of IL-10 than monocytes from the more resistant strain C57BL/6J. 33 Furthermore, IL-10 deficiency in C57BL/6J mice resulted in more severe arthritis. 28 It is possible that reduced IL-10 production by C3H/HeJ mice explains their increased susceptibility to arthritis during B. burgdorferi infection.…”

Monocyte p110α phosphatidylinositol 3-kinase regulates phagocytosis, the phagocyte oxidase, and cytokine production

“…Exogenous TNF-␣ has been reported to augment IL-10 production in monocytes [40], and IL-10 has also been demonstrated to suppress LPS-induced IL-6 and IL-12 production [41]. We considered the possibility that enhanced production of TNF-␣ by p110␣-deficient cells might have led to augmented IL-10 production through a paracrine effect and that this may have led to suppression of IL-6 and IL-12.…”

“…Exogenous TNF-␣ has been reported to augment IL-10 production by monocytes [40]. We considered the possibility that enhanced TNF-␣ production by p110␣-deficient cells might bring about augmented IL-10 production via a paracrine effect.…”