c-Jun Kinase Is a Critical Signaling Molecule in a Neonatal Model of Group B Streptococcal Sepsis

Abstract

Group B streptococcus (GBS) is the major cause of sepsis in newborn infants. In vitro, inactivated GBS stimulates macrophages to produce inflammatory proteins via the TLR adapter protein MyD88. Furthermore, inflammatory cytokine release in response to GBS greatly exceeds that following stimulation with pneumococci. In this study, we attempted to unravel signaling events that are involved in GBS-, but not Streptococcus pneumoniae-stimulated phagocytes to identify molecular targets for adjunctive sepsis therapy. We found that inactivated GBS and S. pneumoniae differed in the activation of the MAPK JNK, but not IκB kinase. Furthermore, JNK was essential for the transcriptional activation of inflammatory cytokine genes in response to GBS. Inhibition of JNK by the anthrapyrazolone SP600125 abrogated GBS-induced cytokine formation via an AP-1- and NF-κB-dependent mechanism without impairing antibacterial properties such as phagocytosis of GBS and the formation of intracellular oxidative species. In contrast, inhibition of the MAPK p38 impaired both antibacterial processes. In a neonatal mouse model of GBS sepsis SP600125 inhibited the inflammatory response and improved survival. In conclusion, JNK plays a major role in the inflammatory, but not in the direct antibacterial response to inactivated GBS, and may thus serve as a rational target for an adjunctive GBS sepsis therapy.

C-Jun NH2 terminal kinase (JNK) is an essential mediator of Toll-like receptor 2-induced corneal inflammation

“…Of particular interest for infectious disease is the selective use of MAPK inhibitors in antiinflammatory versus antimicrobial activity. In a murine model of Group B Streptococcal sepsis, SP600125 blocked cytokine production with no effect on phagocytosis or formation of antibacterial oxidative species [38].…”

Uses for JNK: the Many and Varied Substrates of the c-Jun N-Terminal Kinases

“…There is also an increasing body of literature showing that JNK activation follows bacterial, fungal, prion, parasitic, or viral infections. Under these circumstances, JNK activation may influence important cellular consequences, such as alterations in gene expression (1,53,59,162,167,176,199,294,325,326,346), cell death (58,89,137,139,169,193,243,293), viral replication, persistent infection or progeny release (215,224,251,260), or altered cellular proliferation (178). The exact mechanism of JNK activation under each of these circumstances remains to be elucidated fully, although there may be involvement of Toll-like receptors, direct pathway modulation through interaction with upstream protein regulators, or the activation following an ER stress response (79,87,110,124,143,191,253,261,279,294,312).…”

“…It is important that although the JDP2 sequence apparently contains a classic JBD consensus sequence within its leucine zipper domain (i.e., K 136 NEKQH LIYMLNLH 149 [residues of the consensus are shown in bold]), the site of interaction was mapped to the JDP2 C-terminal region beyond residue 153 (155). Indeed, a 14-amino-acid fragment derived from the JDP2 sequence (i.e., JDP2 [150][151][152][153][154][155][156][157][158][159][160][161][162][163] ), when added to the transcription factor ATF3, which is usually not a JNK substrate, facilitated JNK phosphorylation of ATF3; this sequence alone was therefore sufficient for JNK interaction (155). In contrast to c-Jun-binding partners such as c-Fos or ATF2, JDP2 acts as a repressor at the AP-1 site, and it also inhibits Ras-driven transformation of NIH 3T3 cells and suppresses tumor formation in vivo in a PC3 cell xenograft model (128).…”

Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria

“…GBS and encapsulated E. coli are major causes of sepsis and meningitis in the newborn and are being increasingly associated with invasive disease in the adult population (24). Moreover, several signal transduction pathways contributing to innate resistance against these bacteria have been elucidated recently (25)(26)(27)(28).…”