Elevated levels of TNF in the joints of adjuvant arthritic rats

Smith-Oliver, Tracey; Noël, Laurence; Stimpson, SA; Yarnall, David P.; Connolly, Kevin M.

doi:10.1016/1043-4666(93)90060-i

Cited by 58 publications

(37 citation statements)

References 25 publications

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“…Numerous studies have demonstrated that TNF-␣ concentrations are markedly elevated at the site of local inflammation in rodents (e.g., Ford et al, 1989;Ferrandiz and Foster, 1991;Karalis et al, 1991;Smith-Oliver et al, 1993;Sekut et al, 1994); however, the relationship between tissue and circulating levels of TNF-␣ is controversial (Franks et al, 1991;Remick, 1991;Tracey and Cerami, 1992;Sekut et al, 1994). Although we found detectable levels of bioactive TNF-␣ in the plasma of control intravenously cannulated rats, there was no change in its concentration during acute local inflammation over the time course that we showed to be relevant to the cerebral TNF-␣-mediated increases in HPA activity.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Tumor Necrosis Factor-α Action within the CNS Markedly Reduces the Plasma Adrenocorticotropin Response to Peripheral Local Inflammation in Rats

et al. 1997

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The present study tested the hypothesis that the cytokine tumor necrosis factor-α (TNF-α) is an important CNS mediator of the hypothalamo-pituitary-adrenal (HPA) axis response to local inflammation in the rat. Recombinant murine TNF-α administered directly into the cerebroventricles of normal rats produced a dose-dependent increase in plasma adrenocorticotropin (ACTH) concentration. Local inflammation induced by the intramuscular injection of turpentine (50 μl/100 gm body weight) also produced an increase in plasma ACTH, peaking at 160–200 pg/ml at 7.5 hr after injection (compared with 10–30 pg/ml in controls). Intracerebroventricular pretreatment with either 5 μl of anti-TNF-α antiserum or 1–50 μg of soluble TNF receptor construct (rhTNFR:Fc) reduced the peak of the ACTH response to local inflammation by 62–72%. In contrast, intravenous treatment with the same doses of anti-TNF-α or rhTNFR:Fc had no significant effect on the ACTH response to local inflammation. Although these data indicated an action of TNF-α specifically within the brain, no increase in brain TNF-α protein (measured by bioassay) or mRNA (assessed using eitherin situhybridization histochemical or semi-quantitative RT-PCR procedures) was demonstrable during the onset or peak of HPA activation produced by local inflammation. Furthermore, increased passage of TNF-α from blood to brain seems unlikely, because inflammation did not affect plasma TNF-α biological activity. Collectively these data demonstrate that TNF-α action within the brain is critical to the elaboration of the HPA axis response to local inflammation in the rat, but they indicate that increases in cerebral TNF-α synthesis are not a necessary accompaniment.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Tumor Necrosis Factor-α Action within the CNS Markedly Reduces the Plasma Adrenocorticotropin Response to Peripheral Local Inflammation in Rats

et al. 1997

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“…In this model, rolipram and CP-77059 not only reduced tissue oedema but also inhibited radiological changes in the bone. In a previous paper we compared ankle swelling and joint TNF-ft levels in arthritic rats treated with non-steroidal anti-inflammatory drugs or immunosuppressive compounds [17]. ll will also be important to address the relationship belween joint protection and joint TNF-a levels in arthritic rats treated with PDE-IV inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…The rat adjuvant arthritis model mimics many aspects of human rheumatoid arthritis, including elevated levels of TNF'-a in the arthritic joint [17,24]. In this model, rolipram and CP-77059 not only reduced tissue oedema but also inhibited radiological changes in the bone.…”

Section: Discussionmentioning

confidence: 99%

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Anti-inflammatory activity of phosphodiesterase (PDE)-IV inhibitors in acute and chronic models of inflammation

Sekut

Yarnall

Stimpson

et al. 1995

Clinical and Experimental Immunology

116

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SUMMARYInhibitors of cyclic nucleotide phosphodiesterases are known to suppress lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-Q) production in vitro In human monocytes. The most potent of these have selectivity for type IV PDEs, suggesting that this class of PDE is the major type involved in the regulation of human TNF-« production. Using compounds of two distinct chemical structural classes, a quinazolincdionc (CP-77 059) and a 4 arylpyrrolidinone (rolipram). we show here that PDE-IV-specific inhibitors are also potent in stippressing LPSinduced TNF-rv production in vitro in sodium periodate-clicited murine macrophages (IC'syS of 1 and 33, respectively). We then report the in vivo anti-inflammatory effect of PDE-IV inhibition in five murine models of inflammation: (i) elevation of serum TNF-a induced by a subtethal LPS injection; {ii) LPS-indueed endotoxic shock; (iii) LPS/galactosamine-induced endotoxic shock; (iv) carrageenan-induced paw oedema; and (v) adjuvant arthritis. Following a sublcthal {5/(g/mouse) injection of LPS, serum TNF-a levels in miee peaked sharply, reaching concentrations of 3-12ng/ ml 90 min after injection. In this sublethal LPS assay. CP-77 059 was about 30 times more potent than rolipram, with a minimum effective dose of 01 mg/kg versus 3 mg/kg for rolipram. This rank order is in keeping with the relative in vitro ICsoS for CP-77059 and rolipram, as well as their relative Ki against the human PDE-IV enzyme (46 nM and 220 nM, respectively). In LPS-induced endotoxic shock, rolipram and CP-77 059 at relatively high doses of 30 and 10 mg/kg. respectively. significantly reduced serum TNF-ft levels, and also inhibited mortality 66%. In the LPS/ galactosamine shock model, in which mice are rendered exquisitely sensitive to LPS by coinjection with galaetosamine. oniy 01 ^ig of LPS/mouse Is necessary for serum TNF-cv elevation and death. Both rolipram and the CP-77059 caused dose-dependent reduction of serum TNF-rt and lethality. In the carrageenan-induced paw oedema model, in which there is a pronounced local TNF-(v response {without a serum TNF-a elevation), rolipram significantly inhibited paw swelling as well as localized TNF-cv levels in the paw. In the adjuvant arthritis model, a chronic model of inflammation also possessing localized TNF-a elevation in the inflamed paw, rolipram and CP-77059 suppressed ankle swelling and radiological evidence of joint damage. These data are consistent with a major role for PDE-IV in regulation of TNF-a production and inflammatory responses in murine systems. It suggests a potential therapeutic use for PDE-IV-specific inhibitors in inflammatory disease such as rheumatoid arthritis, septic shock and other inflammatory diseases where TNF-a has been postulated to be a contributing factor in the pathology ofthe disease.

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“…IL-1 can also accelerate the development of type II collagen-induced arthritis (CIA) in susceptible but not resistant strains of mice [18]. Similarly, TNF which is found at elevated levels in the joints of adjuvant arthritic rats [19] will also induce a more severe disease if injected intraarticularly into the joints of rats with CIA [20][21][22]. Although these and other studies conflrmed the catabolic and/or chemotactic properties of these cytokines in vivo, they did not address the degree to which endogenous production of these cytokines contributes to the development and/or progression of arthritis in susceptible animal models.…”

Section: Potentiating Effects Of Cytokines In Experimental Arthritismentioning

confidence: 99%

Role of cytokines in experimental arthritis

Brennan¹

1994

Clinical and Experimental Immunology

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Elevated levels of TNF in the joints of adjuvant arthritic rats

Cited by 58 publications

References 25 publications

Inhibition of Tumor Necrosis Factor-α Action within the CNS Markedly Reduces the Plasma Adrenocorticotropin Response to Peripheral Local Inflammation in Rats

Inhibition of Tumor Necrosis Factor-α Action within the CNS Markedly Reduces the Plasma Adrenocorticotropin Response to Peripheral Local Inflammation in Rats

Anti-inflammatory activity of phosphodiesterase (PDE)-IV inhibitors in acute and chronic models of inflammation

Role of cytokines in experimental arthritis

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