PGG-Glucan activates NF-κB-like and NF-IL-6-like transcription factor complexes in a murine monocytic cell line

Abstract

PGG-Glucan (Betafectin®) is a novel soluble β-glucan immunomodulator that enhances leukocyte microbicidal activities without inducing inflammatory cytokines. Although several different receptors for soluble and particulate β-glucans have been described, the signal transduction pathway(s) used by soluble β-glucans have not been elucidated. We report that in a murine monocytic cell line (BMC2.3) PGG-Glucan activates nuclear factor-κB (NF-κB)-like and NF-interleukin-6 (IL-6)-like transcription factors. Electrophoretic mobility shift assays showed that PGG-Glucan activation of the factors is time- and concentration-dependent. The NF-κB-like complex includes subunit p65 (rel-A) as one of its components, but apparently not p50 (κB1), p52 (κB2), p68 (rel-B), or p75 (C-rel) family members. The NF-IL-6-like complex contains subunit C/EBP-β (NF-IL-6α) as one of its components, but apparently not C/EBP-α or C/EBP-δ (NF-IL-6β). As expected, lipopolysaccharide (LPS) activated p65/p50 NF-κB and C/EBP-β NF-IL-6 complexes, increased the nuclear titer of p65 and p50 antigens, and increased cytokine (IL-1β, tumor necrosis factor α) mRNA production. In contrast, PGG-Glucan increased the nuclear titer of p65, but apparently not p50, and did not induce cytokine mRNA production, These data demonstrate that PGG-Glucan utilizes signal transduction pathways different from those used by LPS. The data suggest that activation of the PGG-Glucan-stimulated factors is not sufficient to stimulate cytokine mRNA transcription.

Modulation of the Phosphoinositide 3-Kinase Pathway Alters Innate Resistance to Polymicrobial Sepsis

“…Although any or all of these conclusions may be valid, they also presented a paradox, in that glucans are well known immune stimulators (30). There is a mild inflammatory response associated with glucan-induced immune stimulation (31,32). The pathophysiology of sepsis/septic shock suggests that after severe injury or infectious challenge the host responds by overexpressing inflammatory mediators resulting in a systemic inflammatory response that may produce severe shock, multiorgan failure, and death (1).…”

Activation of rat macrophages by Betafectin PGG-glucan requires cross-linking of membrane receptors distinct from complement receptor three (CR3)

“…PGG-glucan has broad antiinfective activities in a variety of animal models [21][22][23][24][25] and has been shown to reduce the incidence of post-surgical infections in upper gastrointestinal surgery patients [26,27, and E. P. Dellinger et al, unpublished results]. In contrast to most other ␤-glucan preparations, PGG-glucan does not directly stimulate leukocyte microbicidal functions in vitro, but rather primes or enhances their responsiveness to bacteria and other stimuli [3,29]. PGG-glucan also does not directly stimulate or enhance the production of pro-inflammatory cytokines either in vitro or in vivo [3,24,29,30,31].…”

“…In contrast to most other ␤-glucan preparations, PGG-glucan does not directly stimulate leukocyte microbicidal functions in vitro, but rather primes or enhances their responsiveness to bacteria and other stimuli [3,29]. PGG-glucan also does not directly stimulate or enhance the production of pro-inflammatory cytokines either in vitro or in vivo [3,24,29,30,31].…”

Pneumocystis carinii Cell Wall β-Glucans Initiate Macrophage Inflammatory Responses through NF-κB Activation

“…Zymosan, a commonly studied ␤-glucan source prepared from the nonpathogenic fungus Saccharomyces cerevisiae and other soluble nonpathogenic glucans activate nuclear factor NF-B in cell lines (23)(24)(25)(26). Whether NF-B participates in signaling macrophage inflammatory activation to release TNF␣ following stimulation with cell wall ␤-glucans derived from P. carinii and whether such signaling can be modified pharmacologically are currently unknown.…”