Mitogen-Activated Protein Kinases and NF-κB Are Involved in TNF-α Responses to Group B Streptococci

Mancuso, Giuseppe; Midiri, Angelina; Beninati, Concetta; Piraino, Giovanna; Valenti, Andrea; Nicocia, Giacomo; Teti, Diana; Cook, James A.; Teti, Giuseppe

doi:10.4049/jimmunol.169.3.1401

Cited by 69 publications

(57 citation statements)

References 69 publications

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“…Thus, we determined the effect of SP600125 on p38 activation in response to GBS. As previously reported, p38 is rapidly phosphorylated in GBS-stimulated mouse macrophages (10,20). Interestingly, this activation was not inhibited by SP600125; instead, we observed some increased activation when the macrophages were incubated in the presence of GBS and SP600125 as compared with GBS alone (Fig.…”

Section: Sp600125 Inhibits Ap-1 Activation Without Affecting Related supporting

confidence: 66%

“…A tight balance of these counteracting effects seems essential for the fate of the septic patient because both the inflammatory cytokine storm and the predominantly anti-inflammatory immune paralysis can be lethal (26). The delicate sensing system of TLRs occupies a key position in the response to GBS because the TLR adapter protein MyD88 is essential for an inflammatory activation by GBS, both in vitro and in vivo (10,20). Downstream of GBS-TLRMyD88 interaction, the MAPKs extracellular regulated kinase and p38 are activated by a process that probably involves the signaling intermediates TNFR-associated factor 6, evolutionarily conserved signaling intermediate in Toll pathways, and members of the MAPK kinase family (10,20,(27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

“…NF-B has been described as a critical transcription factor for GBS-induced TNF (10,20). In this study, we aimed to define a distinct NF-B binding site in the TNF promoter that is essential for GBS-induced TNF formation.…”

Section: Gbs and S Pneumoniae Are Similar With Respect To Ib Kinase mentioning

confidence: 99%

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

Kenzel¹,

Mancuso

Malley

et al. 2006

The Journal of Immunology

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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.

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Section: Sp600125 Inhibits Ap-1 Activation Without Affecting Related supporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

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

Kenzel¹,

Mancuso

Malley

et al. 2006

The Journal of Immunology

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“…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).…”

mentioning

confidence: 99%

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

Mancuso

Midiri

Biondo

et al. 2007

The Journal of Immunology

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220

214

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It is known that host cells can produce type I IFNs (IFN-αβ) after exposure to conserved bacterial products, but the functional consequences of such responses on the outcome of bacterial infections are incompletely understood. We show in this study that IFN-αβ signaling is crucial for host defenses against different bacteria, including group B streptococci (GBS), pneumococci, and Escherichia coli. In response to GBS challenge, most mice lacking either the IFN-αβR or IFN-β died from unrestrained bacteremia, whereas all wild-type controls survived. The effect of IFN-αβR deficiency was marked, with mortality surpassing that seen in IFN-γR-deficient mice. Animals lacking both IFN-αβR and IFN-γR displayed additive lethality, suggesting that the two IFN types have complementary and nonredundant roles in host defenses. Increased production of IFN-αβ was detected in macrophages after exposure to GBS. Moreover, in the absence of IFN-αβ signaling, a marked reduction in macrophage production of IFN-γ, NO, and TNF-α was observed after stimulation with live bacteria or with purified LPS. Collectively, our data document a novel, fundamental function of IFN-αβ in boosting macrophage responses and host resistance against bacterial pathogens. These data may be useful to devise alternative strategies to treat bacterial infections.

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“…In monocytes and macrophages, LPS is known to stimulate TNF-␣ production by activating mitogen-activated protein (MAP) kinase subtypes including extracellular signal-regulated kinase (ERK), p38 kinase, and c-Jun N-terminal kinase (23)(24)(25). Among the MAP kinase subtypes, specific inhibitors for p38 kinase have been shown to inhibit LPS-induced TNF-␣ production (26 -28).…”

mentioning

confidence: 99%

α-Melanocyte-stimulating Hormone Inhibits Lipopolysaccharide-induced Tumor Necrosis Factor-α Production in Leukocytes by Modulating Protein Kinase A, p38 Kinase, and Nuclear Factor κB Signaling Pathways

Yoon

Goh

Chun

et al. 2003

Journal of Biological Chemistry

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The neuropeptide ␣-melanocyte-stimulating hormone (␣-MSH) inhibits inflammation by down-regulating the expression of proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣) in leukocytes via stimulation of ␣-MSH cell surface receptors. However, the signaling mechanism of ␣-MSH action has not yet been clearly elucidated. Here, we have investigated signaling pathways by which ␣-MSH inhibits lipopolysaccharide (LPS)-induced TNF-␣ production in leukocytes such as THP-1 cells. We focused on the possible roles of protein kinase A (PKA), p38 kinase, and nuclear factor B (NF B) signaling. In THP-1 cells, LPS is known to activate p38 kinase, which in turn activates NF B to induce TNF-␣ production. We found that pretreatment of cells with ␣-MSH blocked LPS-induced p38 kinase and NF B activation as well as TNF-␣ production. This response was proportional to ␣-MSH receptor expression levels, and addition of an ␣-MSH receptor antagonist abolished the inhibitory effects. In addition, ␣-MSH treatment activated PKA, and PKA inhibition abrogated the inhibitory effects of ␣-MSH on p38 kinase activation, NF B activation, and TNF-␣ production. Taken together, our results indicate that stimulation of PKA by ␣-MSH causes inhibition of LPS-induced activation of p38 kinase and NF B to block TNF-␣ production.

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Mitogen-Activated Protein Kinases and NF-κB Are Involved in TNF-α Responses to Group B Streptococci

Cited by 69 publications

References 69 publications

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

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

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

α-Melanocyte-stimulating Hormone Inhibits Lipopolysaccharide-induced Tumor Necrosis Factor-α Production in Leukocytes by Modulating Protein Kinase A, p38 Kinase, and Nuclear Factor κB Signaling Pathways

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