Complement Activates the c-Jun N-Terminal Kinase/Stress-Activated Protein Kinase in Glomerular Epithelial Cells

Peng, Hongwei; Takano, Tomoko; Papillon, Joan; Bijian, Krikor; Khadir, Abdelkrim; Cybulsky, Andrey V.

doi:10.4049/jimmunol.169.5.2594

Cited by 50 publications

(44 citation statements)

References 40 publications

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“…In an earlier study, we demonstrated that complementinduced activation of JNK is dependent on arachidonic acid release and production of superoxide (32). In contrast to the activation of ERK, cytochalasin D, latrunculin B, and calyculin A did not inhibit complement-induced JNK activation (Fig.…”

Section: A-cmentioning

confidence: 99%

“…Complementmediated cytolysis was determined by measuring release of lactate dehydrogenase (LDH), similarly to the method described previously (12,32). Specific release of LDH was calculated as [NS Ϫ HIS]/ [100 Ϫ HIS], where NS represents the percent of total LDH released into cell supernatants in incubations with NS, and HIS is the percent of total LDH released into cell supernatants in incubations with HIS.…”

Section: Methodsmentioning

confidence: 99%

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Activation of the extracellular signal-regulated kinase by complement C5b-9

Cybulsky¹,

Takano²,

Papillon³

et al. 2005

American Journal of Physiology-Renal Physiology

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Extracellular signals may be transmitted to nuclear or cytoplasmic effectors via the mitogen-activated protein kinases. In the passive Heymann nephritis (PHN) model of membranous nephropathy, complement C5b-9 induces glomerular epithelial cell (GEC) injury, proteinuria, and activation of phospholipases and protein kinases. This study addresses the complement-mediated activation of the extracellular signal-regulated kinase (ERK). C5b-9 induced ERK threonine202/tyrosine204 phosphorylation (which correlates with activation) in GEC in culture and PHN in vivo. Expression of a dominant-inhibitory mutant of Ras reduced complement-mediated activation of ERK, but activation was not affected significantly by downregulation of protein kinase C. Complement-induced ERK activation resulted in phosphorylation of cytosolic phospholipase A2 and was, in part, responsible for phosphorylation of mitogen-activated protein kinase-associated protein kinase-2, but did not induce phosphorylation of the transcription factor, Elk-1. Activation of ERK was attenuated by drugs that disassemble the actin cytoskeleton (cytochalasin D, latrunculin B), and these compounds interfered with the activation of ERK by mitogen-activated protein kinase kinase (MEK). Overexpression of a constitutively active RhoA as well as inhibition of Rho-associated kinase blocked complement-mediated ERK activation. Complement cytotoxicity was enhanced after disassembly of the actin cytoskeleton but was unaffected after inhibition of complement-induced ERK activation. However, complement cytotoxicity was enhanced in GEC that stably express constitutively active MEK. Thus complement-induced ERK activation depends on cytoskeletal remodelling and affects the regulation of distinct downstream substrates, while chronic, constitutive ERK activation exacerbates complement-mediated GEC injury.

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Section: A-cmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Activation of the extracellular signal-regulated kinase by complement C5b-9

Cybulsky¹,

Takano²,

Papillon³

et al. 2005

American Journal of Physiology-Renal Physiology

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“…Each of the MAPK family of proteins, including ERKs, p38 MAPKs, and JNKs, has a demonstrable importance in the pathogenesis of cancer, and each is significantly activated by the MAC with resulting cellular proliferation (51,54,55,61,62). Other oncogenic targets activated by the MAC include the phosphoinositide 3-kinase pathway (55), Ras (63), p70 S6 kinase (51), and the Janus-activated kinase-signal transducer and activated transcription pathway (56).…”

Section: Complement Promotes Oncogenesismentioning

confidence: 99%

Cancer and the Complement Cascade

Rutkowski

Sughrue

Kane

et al. 2010

Molecular Cancer Research

225

249

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Despite significant research on the role of inflammation and immunosurveillance in the immunologic microenvironment of tumors, little attention has been given to the oncogenic capabilities of the complement cascade. The recent finding that complement may contribute to tumor growth suggests an insidious relationship between complement and cancer, especially in light of evidence that complement facilitates cellular proliferation and regeneration. We address the hypothesis that complement proteins promote carcinogenesis and suggest mechanisms by which complement can drive the fundamental features of cancer. Evidence shows that this diverse family of innate immune proteins facilitates dysregulation of mitogenic signaling pathways, sustained cellular proliferation, angiogenesis, insensitivity to apoptosis, invasion and migration, and escape from immunosurveillance. Given that the traditionally held functions for the complement system include innate immunity and cancer defense, our review suggests a new way of thinking about the role of complement proteins in neoplasia.

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“…Incubation of cultured GEC with complement stimulated superoxide production via the NADPH oxidase. The mechanism involves activation of cPLA 2 and release of AA (100).…”

Section: Reactive Oxygen Speciesmentioning

confidence: 99%

Experimental membranous nephropathy redux

Cybulsky

Quigg²,

Salant³

2005

American Journal of Physiology-Renal Physiology

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115

133

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Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Active and passive Heymann nephritis (HN) in rats are valuable experimental models because their features so closely resemble human MN. In HN, subepithelial immune deposits form in situ as a result of circulating antibodies. Complement activation leads to assembly of C5b-9 on glomerular epithelial cell (GEC) plasma membranes and is essential for sublethal GEC injury and the onset of proteinuria. This review revisits HN and focuses on areas of substantial progress in recent years. The response of the GEC to sublethal C5b-9 attack is not simply due to disruption of the plasma membrane but is due to the activation of specific signaling pathways. These include activation of protein kinases, phospholipases, cyclooxygenases, transcription factors, growth factors, NADPH oxidase, stress proteins, proteinases, and others. Ultimately, these signals impact on cell metabolic pathways and the structure/function of lipids and key proteins in the cytoskeleton and slit-diaphragm. Some signals affect GEC adversely. Thus C5b-9 induces partial dissolution of the actin cytoskeleton. There is a decline in nephrin expression, reduction in F-actin-bound nephrin, and loss of slit-diaphragm integrity. Other signals, such as endoplasmic reticulum stress, may limit complement-induced injury, or promote recovery. The extent of complement activation and GEC injury is dependent, in part, on complement-regulatory proteins, which act at early or late steps within the complement cascade. Identification of key steps in complement activation, the cellular signaling pathways, and the targets will facilitate therapeutic intervention in reversing GEC injury in human MN.

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Complement Activates the c-Jun N-Terminal Kinase/Stress-Activated Protein Kinase in Glomerular Epithelial Cells

Cited by 50 publications

References 40 publications

Activation of the extracellular signal-regulated kinase by complement C5b-9

Activation of the extracellular signal-regulated kinase by complement C5b-9

Cancer and the Complement Cascade

Experimental membranous nephropathy redux

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