Cyclophilin B Attenuates the Expression of TNF-α in Lipopolysaccharide-Stimulated Macrophages through the Induction of B Cell Lymphoma-3

Abstract

Extracellular cyclophilin A (CyPA) and CyPB have been well described as chemotactic factors for various leukocyte subsets, suggesting their contribution to inflammatory responses. Unlike CyPA, CyPB accumulates in extracellular matrixes, from which it is released by inflammatory proteases. Hence, we hypothesized that it could participate in tissue inflammation by regulating the activity of macrophages. In the current study, we confirmed that CyPB initiated in vitro migration of macrophages, but it did not induce production of proinflammatory cytokines. In contrast, pretreatment of macrophages with CyPB attenuated the expression of inflammatory mediators induced by LPS stimulation. The expression of TNF-α mRNA was strongly reduced after exposure to CyPB, but it was not accompanied by significant modification in LPS-induced activation of MAPK and NF-κB pathways. LPS activation of a reporter gene under the control of TNF-α gene promoter was also markedly decreased in cells treated with CyPB, suggesting a transcriptional mechanism of inhibition. Consistent with this hypothesis, we found that CyPB induced the expression of B cell lymphoma-3 (Bcl-3), which was accompanied by a decrease in the binding of NF-κB p65 to the TNF-α promoter. As expected, interfering with the expression of Bcl-3 restored cell responsiveness to LPS, thus confirming that CyPB acted by inhibiting initiation of TNF-α gene transcription. Finally, we found that CyPA was not efficient in attenuating the production of TNF-α from LPS-stimulated macrophages, which seemed to be due to a modest induction of Bcl-3 expression. Collectively, these findings suggest an unexpected role for CyPB in attenuation of the responses of proinflammatory macrophages.

Insights into peptidyl-prolyl cis–trans isomerase structure and function in immunocytes

“…CyPB induces expression of Bcl-3 and is accompanied by a decrease in the binding of NF-B p65 to the TNF-␣ promoter. This confirms that CyPB inhibits gene transcription [119].…”

Resveratrol Reduces the Proinflammatory Effects and Lipopolysaccharide- Induced Expression of HMGB1 and TLR4 in RAW264.7 Cells

“…RR047A, Takara), according to the manufacturer's instructions. The transcript of GAPDH (control) was used as normalization for total mRNA input and to confirm efficiency of cDNA synthesis [25]. A relative quantitative real-time PCR analysis was performed on aliquots of the cDNA production, using SYBR Premix EX Taq™ II (Code.…”

Cyclophilin-B Modulates Collagen Cross-linking by Differentially Affecting Lysine Hydroxylation in the Helical and Telopeptidyl Domains of Tendon Type I Collagen

“…CypB, encoded by the PPIB gene, is a peptidyl-prolyl cis-trans-isomerase and a component of the prolyl-3-hydroxylase complex. It is a multifunctional protein implicated in recessive OI (21)(22)(23)(24), inflammation (25), and cancer (26). Our recent study on Ppib Ϫ/Ϫ (hereafter referred to as CypB KO) mice (27) provided evidence that CypB deficiency affects collagen cross-linking by diminishing Lys hydroxylation specifically at the helical crosslinking sites in bone type I collagen.…”